Hypokalemic paralysis in Sjgrens syndrome associated with Distal

Hypokalemic paralysis in SjÖgren’s syndrome associated with Distal renal tubular acidosis Ji Eun Lee, Kang Ji Ko, Jin Ho Shin, Young Joo Kwon, Heui-Jung Pyo, Jin Kim* Department of Internal Medicine, College of Medicine, Korea University Department of Anatomy, Catholic University Medical College* Seoul, Korea

CASE 1 손 0 이

Identification and Present illness • S/A : F/25 • C. C. : Proximal muscle weakness (onset : 1 day ago) • P. I. : 20 kg weight loss for 1 years Poor oral intake for 10 days Proximal muscle weakness for 1 day

Past Hx & Systemic review • PHx : DM(-), HTN(-), Tbc(-), HBV carrier(+) Spontaneous abortion(-), Medication(-) • SHx : Alcohol(-) Smoking(-) • FHx : N-C • Systemic review general weakness(+), dry mouth(-), dry eye(-) arthralgia(-), Raynaud’s phenomenon(-) dysuria(-), frequency(-), residual urine sensation(-)

Physical examination • BT 36℃, PR 60/min, RR 20/min, BP 110/70 mm. Hg • Acute ill looking, alert mentality • Anemic conjunctiva, not icteric sclera • Dry tongue and oral mucosa • No specific findings on chest and abdominal exam • Symmetric motor weakness in U/L ext. (Gr IV) • No sensory change and No pathologic reflex

Laboratory finding (1) • CBC 6900/u. L-8. 8 g/d. L-222, 000/u. L • BUN/Cr 14/0. 7 mg/d. L, Osm 289 m. Osm/kg • Na 136 m. Eq/L, K 1. 7 m. Eq/L, Cl 115 m. Eq/L, Ca 9. 3 mg/d. L • U/A SG 1. 010, p. H 7. 5, PRO 30 mg/d. L RBC 0 -1/HPF, WBC 0 -1/HPF • Urine Na-K-Cl 41 -14 -46 m. Eq/L, Osm 216 m. Osm/kg • ABGA p. H 7. 304, p. CO 2 25. 4 mm. Hg, p. O 2 111. 4 mm. Hg HCO 3 - 12. 7 mmol/L, Sa. O 2 98. 9%

Laboratory finding (2) • Anion gap = [Na+]-[Cl-]-[HCO 3 -] = 8. 3 mmol/L (normal : 8 -16) • Urine anion gap = [Na+]+[K-]-[Cl-] = 9 mmol/L(>0) • TTKG 13. 2

Initial EKG

Initial Chest PA

Abdominal sono

Impression (1) Muscle weakness Hypokalemia Hypokalemic paralysis

Impression (2) Metabolic acidosis Hypokalemia Distal RTA Normal anion gap Urine anion gap > 0 Urine p. H > 5. 5

Ammonium chloride loading test Blood p. H Blood t. CO 2 Blood HCO 3 Urine p. H Basal 2 hr 4 hr 6 hr 7. 361 14. 3 11. 9 7. 5 7. 274 14. 0 13. 2 7. 5 7. 131 13. 2 7. 015 7. 190 15. 3 14. 3 7. 104

Bicarbonate loading test Blood p. H Urine p. H Blood p. CO 2 Urine p. CO 2 Blood HCO 3 Urine HCO 3 U-B p. CO 2 Basal 30 min 90 min 7. 231 7. 203 37. 0 34. 1 15. 5 13. 4 - 2. 9 7. 273 7. 282 36. 8 37. 2 17. 0 17. 5 - 0. 4 7. 253 7. 247 42. 6 39. 7 18. 8 17. 3 - 2. 9

Light microscopic findings

Immunohistochemistry of Aquaporin control patient

Immunohistochemistry of Na+/K+-ATPase α 1 control patient

Immunohitochemistry of Na+/K+-ATPase β 1 control patient

Immunohitochemistry of H+-ATPase control patient

Immunohitochemistry of Cl-/HCO 3 - exchanger control patient

Laboratory findings (3) • Ig. G 2080 mg/d. L, Ig. A 266 mg/d. L, Ig. M 85 mg/d. L • FANA(+) 1: 80 homogeneous pattern • Anti-ds DNA(-), C 3 67. 7 mg/d. L, C 4 16. 3 mg/d. L • Anti-SSA/Ro(+), Anti-SSB/La(-) • Anti-RNP(-), Anti-Sm(-) • RF(+), CRP(-), ASLO<200 • HBs. Ag/Hbs. Ab(+/-), Anti-HCV(-), VDRL(-)

Shirmer’s test POSITIVE OD – 3 mm tearflows at 5 min OS - 3 mm tearflows at 5 min Lip biopsy Benign lymphoepithelial lesion, consistent with SjÖgren’s syndrom

Final diagnosis Shirmer’s test(+) Lip biopsy(+) FANA(+), Anti-Ro(+) SjÖgren’s syndrom Distal RTA Normal anion gap MA Urine anion gap > 0 Urine p. H > 5. 5 Ammonium chloride loading test Bicarbonate loading test Immunohistochemical staining

Management & Progress • Sx improvement after IV K replace on the next day • In Day #8, K 3. 7 m. Eq/L, HCO 3 - 13. 3 m. Eq/L during oral potassium and bicarbonate supplements • Discharged with medication of sodium bicarbonate 6 g/day and oral KCl 50 m. Eq/day • After follow-up with medication for 4 years, stable and K 3. 6 m. Eq/L, t. CO 2 26. 4 m. Eq/L

CASE 2 유 0 남

Identification and Present illness • S/A : F/33 • C. C. : Motor weakness of upper and lower ext. (onset : 1 day ago) • P. I. : General weakness for 1 mo Herb medicaiton for 10 days Motor weakness and paralysis before 1 day ago

Past Hx & Systemic review • PHx : DM(-), HTN(-), Tbc(-), Hepatitis(-) Spontaneous abortion(-) • SHx : Alcohol(-) Smoking(-) • FHx : N-C • Systemic review weight loss(+) : 5 kg/year dry mouth(+), dry eye(+), arthralgia(-) Raynaud’s phenomenon(-) dysuria(-), frequency(-), residual urine sensation(-)

Physical examination • BT 36. 4℃, PR 80/min, RR 20/min, BP 100/60 mm. Hg • Acute ill looking, alert mentality • Mild dry tongue and oral mucosa • No specific findings on chest and abdominal exam • Motor weakness in upper and lower extremities (Gr III) • No sensory change and No pathologic reflex

Laboratory finding (1) • CBC 10, 400/u. L-14. 6 g/d. L-304, 000/u. L • BUN/Cr 14/0. 8 mg/d. L, Osm 289 m. Osm/kg • Na 138 m. Eq/L, K 2. 0 m. Eq/L, Cl 110 m. Eq/L, Ca 9. 3 mg/d. L • U/A SG 1. 015, p. H 7. 0, PRO 100 mg/d. L RBC 0 -1/HPF, WBC 0 -1/HPF • Urine Na-K-Cl 59 -14 -64 m. Eq/L, Osm 306 m. Osm/kg • ABGA p. H 7. 324, p. CO 2 30. 8 mm. Hg, p. O 2 117. 2 mm. Hg HCO 3 - 16. 3 mmol/L, Sa. O 2 98. 9%

Laboratory finding (2) • Anion gap = [Na+]-[Cl-]-[HCO 3 -] = 11. 7 mmol/L • Urine anion gap = [Na+]+[K-]-[Cl-] = 9 mmol/L(>0)

Initial Chest PA

Abdominal sono

Impression (1) Dry eye Dry mouth SjÖgren’s syndrom

Laboratory findings (3) • Ig. G 2100 mg/d. L, Ig. A 313 mg/d. L, Ig. M 139 mg/d. L • FANA(+) 1: 40 speckled pattern • Anti-ds DNA(-), C 3 76. 5 mg/d. L, C 4 19. 3 mg/d. L • Anti-SSA/Ro(+), Anti-SSB/La(-) • Anti-RNP(-), Anti-Sm(-) • RF(+), CRP(-), ASLO<200 • HBs. Ag/Hbs. Ab(-/+), Anti-HCV(-), VDRL(-) • TFT, Cortisol, ACTH : WNL

Shirmer’s test POSITIVE OD – 2 mm/5 min OS - 2 mm/5 min

Sialography

Impression (2) Metabolic acidosis Hypokalemia Distal RTA Normal anion gap Urine anion gap > 0 Urine p. H > 5. 5

Ammonium chloride loading test Basal Blood p. H Blood t. CO 2 Blood HCO 3 Urine p. H 7. 387 19. 0 18. 1 7. 0 2 hr 7. 0 4 hr 6 hr 7. 0 7. 323 16. 6 15. 7 7. 0

Fianl diagnosis FANA(+), Anti-Ro(+) Shirmer’s test(+) Sialography Dry eye and Dry mouth SjÖgren’s syndrom Distal RTA Normal anion gap MA Urine anion gap > 0 Urine p. H > 5. 5 Ammonium chloride loading test

Management & Progress • Sx improvement after K replace on the next day • HD#6, K 3. 5 m. Eq/L, t. CO 2 18. 8 m. Eq/L -> Discharged • Discharged with medication of oral KCl 16 m. Eq and Na. HCO 3 4 g/day and oxiklorin 200 mg/day • After 1 yr, K 3. 6 m. Eq/L, t. CO 2 24. 1 m. Eq/L

REVIEW

SjÖgren’s syndrome

Pathogenesis • Slowly progressive, autoimmune disease affecting exocrine glands • Lymphocyte infiltrate replace epithelium decreased exocrine secretions (exocrinopathy) • Autoantibodies : Ro(SS-A), La(SS-B)

Clinical feature • Mucosal dryness : sicca, xerostomia, xerotrachea, vaginal dryness • Major salivary gland enlargement • Nonerosive polyarthritis • Extraglandular invlove : lung, kidney, liver, and blood vessel • Increased risk of lymphoid malignancy

Diagnosis Ocular symptom Oral symptom dry eye > 3 mon dry mouth > 3 mon No SS Ocular signs Positive Shirmer test Rose Bengal score >4 Histopathology SS Autoantibody Ro(SS-A), La(SS-B) SS ANA, RF Subjective salivary gland test No SS SS

Renal involvement in primary SjÖgren’s syndrome • Approximately 18 -67% of SjÖgren’s syndrome • Abnormal urine acidification test in 35%-50% ® hyposthenuria, hypokalemia, distal RTA • renal stone, nephrocalcinosis • less commonly, proximal RTA with Fanconi’s syndrome • Renal Bx reveals interstitial lymphocytic infiltration

Type 1 (Distal) RTA

Hyperchlormic acidosis with hypokalemia Urine anion gap Negative Positive Extrarenal causes (diarrhea) Urine p. H Consider Proximal RTA > 5. 5 Distal RTA < 5. 5 Urine NH 4 & CO 2 after bicarbonate loading

Urine anion gap • Urine anio gap = [Na+] + [K+] – [Cl-] = unmeasured anions – unmeasured cations • NH 4+ : major unmeasured urinary cations • Acidemia in renal failure & Type 1, 4 RTA → Impaired H+ + NH 4+ → Positive urinary AG • But, urine anion gap cannot be used in two conditions ①↑ Unmeasured anion ex. Ketones in ketoacidosis ② Volume depletion (ex. Diarrhea) → ↓distal Na+ delivery → ↓ distal acidification

Urine osmolal gap • When the urine anion gap is positive and it is unclear whether increased excretion of unmeasured anions is responsible. • Urine osmolal gap = measured – calculated urine osm =2 X [NH 4+] (Calculated urine osmolality = 2 X[Na++K+] + [urea nitrogen]/2. 8 + [glucose]/18)

Distal (classic) RTA Secretory defect Permeability defect H+ backleak H+-ATPase defect H+, K+-ATPase defect Acid excretion Urinary HCO 3 loss Plasma AG : normal Urine AG > 0 Urine p. H > 5. 5

Etiology (1) • Primary Idiopathic or sporadic • Hereditary Familial, including hypercalciuria as the primary abnormality Marfan’s syndrome Wilson’s disease Ehlers-Danlos syndrome

Etiology (2) • Disorders of calcium metabolism and nephrocalcinosis Idiopathic or familial hypercalciuria Primary hyperparathyroidism Hypervitaminosis D, Medullary sponge kidney • Autoimmune disease SjÖgren’s syndrome, RA, SLE Chronic active hepatitis, PBC Hypergammaglobulinemia in cirrhosis Thyroiditis

Etiology (3) • Drugs and toxins Amphotericin B, Ifofamide, Lithium carbonate, Analgesic abuse, Light chains in multiple myeloma Toluene • Associated with hyperkalemia Urinary tract obstruction Sickle cell anemia Renal transplant rejection Systemic lupus erythematosus • Marked volume depletion of any cause

Clinical manifestation • Often asymptomatic • Related to stone disease • Related to severe acidemia (dyspnea, hyperpnea, ventricular arrhythmia decrease in ventricular function, lethargy to coma) • Related to hypokalemia (weakness, fatigue, polyuria, polydipsia) • Impaired growth in children

Diagnosis • Normal anion gap metabolic acidosis & urine p. H > 5. 3 in adults, or 5. 6 in children (in the absence of infection with a urea-splitting organism) • Response to raising the plasma HCO 3 concentration with Na. HCO 3 (infused at a rate of 0. 5 to 1. 0 meq/kg/h) → constant urine p. H & FE HCO 3 -

Ammonium chloride loading test • When acidosis is not severe & urine p. H is equivocal • 0. 1 g(1. 9 mmol) per Kg of body weight • Blood & urine p. H repeatedly over next 6 hr • Although systemic acidosis worsen, urine p. H does not fall below 5. 5 • UTI must not be present during test!

Bicarbonate loading test • Increment in urinary p. CO 2 : sensitive index of H+ secretion rate : HCO 3 - + H+ H 2 CO 3 H 2 O + CO 2 • IV or oral administration of bicarbonate Check urinary p. CO 2 • Normal response : increase urinary p. CO 2 to more than 60 mm. Hg : U - B p. CO 2 > 20 mm. Hg

Interpretation • Proximal RTA ® reduce urinary p. H < 5. 5 during acid loading • Distal RTA not reduce urinary p. H < 5. 5 during acid loading ® low U-B p. CO 2 during bicarbonate loading (secretory defect) ® normal U-B p. CO 2 during bicarbonate loading (gradient defect)

Treatment • In children, 4 -14 m. Eq/kg/day • In adults, 1 -2 m. Eq. L/kg/day • Na. HCo 3 or sodium citrate(Bicitra) • Potassium citrate alone or with sodium citrate(Polycitra) for hypokalemia or for calcium stone disease or nephrocalcinosis