Unusual cause of hypokalemic paralysis in aged men: Sjogren syndrome.

Abstract: Hypokalemic paralysis is a less recognized but reversible disorder in elderly patients. This report describes two elderly Chinese males (age 74 and 78 years) who had progressive muscle weakness and eventually paralysis. Physical examination showed symmetrical flaccid paralysis of extremities. Both had the major biochemical abnormality of profound hypokalemia (1.4 and 1.8 mmol/L) accompanied by high urine [K.sup.+] excretion and hyperchloremic metabolic acidosis. A positive urine anion gap and alkaline urine pointed to the diagnosis of distal renal tubular acidosis. Large doses of potassium chloride supplementation were required to restore muscle strength. Pertinent investigations, including elevated titers of antinuclear antibody and rheumatoid factor, positive anti-Ro antibody, low serum C3 and C4 levels, and delayed saliva excretion on salivary scintigraphy suggested Sjogren syndrome. Despite the lack of sicca syndrome at the initial presentation, both had development of typical sicca syndrome and positive Schirmer test at the 5-month and 1-year follow-up, respectively. Potassium citrate supplement and prednisolone therapy completely corrected the hypokalemia and metabolic acidosis. Extraglandular involvement with distal renal tubular acidosis preceding the typical sicca syndrome may induce hypokalemic paralysis and unveil Sjogren syndrome in elderly males.

Key Words: distal renal tubular acidosis, hypokalemia, paralysis, Sjogren syndrome

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Underlying causes of acute paralysis in the elderly are complicated, including central nervous system ischemia, traumatic spinal cord injury, botulism, Guillain-Barre syndrome, drug-induced paralysis, and various metabolic disorders. Among the metabolic causes, hypokalemic paralysis (HP) comprises a heterogeneous group of disorders characterized by acute reversible muscle weakness and hypokalemia. In addition to potassium ([K.sup.+]) replacement to prevent hypokalemia-related complications such as ventricular arrhythmia and respiratory failure, there should be a rapid and detailed search for the underlying cause to avoid missing treatable disorders. (1)

Sjogren syndrome (SS) is a systemic autoimmune disorder characterized by lymphocytic infiltration of the exocrine glands. Clinically, the first presenting symptoms are typically sicca syndrome. Nevertheless, systemic extraglandular involvement with a diverse spectrum of manifestations can precede the exocrine involvement. Hypokalemic paralysis (HP) resulting from distal renal tubular acidosis (dRTA) as the first presenting feature is an example of severe renal involvement preceding the typical sicca syndrome. (2) SS typically affects middle-aged females (female-to-male ratio 9:1). To the best of our knowledge, only one elderly male with Sjogren syndrome with dRTA manifesting as HP has been reported. (3) Herein, we describe two elderly men who had SS with only HP as the primary presentation.

Case Report

Patient 1

A 74-year-old Chinese male was brought to the emergency department because of generalized muscle weakness that had progressed to paralysis involving all extremities within 3 days. He reported no recent nausea, vomiting, diarrhea, or the use of diuretics and herbs. He did not have hyperthyroidism or any previous episodes of paralysis. The family history was noncontributory.

On physical examination, the patient exhibited clear and cognitive consciousness despite his paralysis. The vital signs showed a blood pressure of 120/78 mm Hg, heart rate of 80 beats/min, respiratory rate of 18 breaths/min, and body temperature of 36.9[degrees]C. No enlarged thyroid gland was palpable. Cardiopulmonary examination was unremarkable. Neurologic examination revealed symmetrical flaccid paralysis and areflexia of all four limbs. No fasciculation, myoclonus, or muscular atrophy was observed. The remainder of the physical examination was unremarkable.

The blood cell counts were all within normal range. His spot urine revealed a pH of 7.6 and proteinuria (++). The biochemical studies are shown in Table 1. Profound hypokalemia (1.4 mmol/L) associated with low urine [K.sup.+] concentration (12.8 mmol/L) but high transtubular potassium concentration gradient (TTKG: 9.1) suggested renal [K.sup.+] wasting. Other serum biochemical findings included a pH of 7.33, [Na.sup.+] 143, [Cl.sup.-] 117, HC[O.sub.3.sup.-] 17.8 mmol/L, urea nitrogen 13.5, and creatinine 1.0 mg/dL. Electrocardiogram revealed prolonged QT interval. The abdominal plain film and sonography both revealed nephrocalcinosis. Hyperchloremic metabolic acidosis accompanied by a positive urine anion gap (UAG: 13.8 mEq/L), alkaline urine, and nephrocalcinosis suggested dRTA.

Aggressive KCI replacement (10 mmol/h) restored his muscle strength when the plasma [K.sup.+] concentration reached 2.6 mmol/L 20 hours later. After the plasma [K.sup.+] level reached 3.5 mmol/L, a NaHC[O.sub.3] loading test (2 mmol/kg) was launched. The result showed a low fractional excretion of HC[O.sub.3.sup.-] (F[E.sub.HC[O.sub.3]]: 2.7%) and low urineblood C[O.sub.2] gradient ([DELTA]U-B PC[O.sub.2]: 14 mm Hg), which confirmed the diagnosis of dRTA.

His immunologic studies showed positive anti-Ro antibody, high antinuclear antibody (ANA: 1:1,280) and rheumatoid factor (272 IU/mL), and low C3 and C4 level (75.4/11.8 mg/dL). Salivary scintigraphy revealed the delayed saliva excretion. The typical sicca syndrome was absent initially. Primary Sjogren syndrome was tentatively diagnosed after the exclusion of secondary causes by detailed physical examination (no joint deformity, skin rash or taut skin), laboratory studies (normal liver enzymes, thyroid function and negative viral markers of hepatitis B and C, EBV, and HIV), and immunologic examinations (negative anti-dsDNA, anti-histone, anti-SM/RNP, anti-neutrophil cytoplasmic antibodies and anti-mitochondrial antibody). He was given potassium citrate (30 mEq/d), active vitamin [D.sub.3] (0.25 [micro]g/d), and prednisolone (0.5 mg/kg per day). The patient did not have any recurrent paralysis or renal function deterioration, and the plasma [K.sup.+] level was maintained between 3.3 and 3.8 mmol/L. During his 5-month follow-up, the patient had development of xerostomia and xerophthalmia and had a positive Schirmer test without evidence of other autoimmune disorders and met the diagnostic criteria of primary Sjogren syndrome (European-American Diagnostic Criteria, 2002). (4)

Patient 2

A 78-year-old Chinese male had sudden onset of lower limb weakness and inability to climb stairs. He had no personal or family history of muscle weakness, arthralgia, use of diuretics, vomiting, diarrhea, weight loss, palpitations, heat intolerance, excessive perspiration, skin rash, dry eye, or dry mouth.

His consciousness was clear, and vital signs were stable. Physical examination showed symmetric proximal and distal muscular weakness with muscular strength grade 3/5 and hyporeflexia in the lower extremities. He also had profound hypokalemia and renal [K.sup.+] wasting. The biochemical studies are shown in Table 1. dRTA was also considered, based on a positive UAG (17.6 mEq/L) and alkaline urine (pH: 7.5) in the presence of hyperchloremic metabolic acidosis (pH: 7.32, [Cl.sup.-]: 113 mmol/L, HC[O.sub.3.sup.-]: 16.1 mmol/L). Intravenous KCI supplementation with total of 220 mmol of [K.sup.+] was needed to restore his muscle strength. Positive anti-Ro, high ANA (1:640), rheumatoid factor (142 IU/mL), and salivary scintigraphy suggested Sjogren syndrome, even without sicca syndrome. Extensive workup also excluded secondary causes of SS. Prednisolone (0.5 mg/kg per day), potassium citrate (30 mEq/d), and active vitamin [D.sub.3] (0.25 [micro]g/d) had ameliorated his clinical symptoms without recurrent paralysis and hypokalemia. During a 1-year follow-up, he also had development of sicca syndrome and positive Schirmer test without evidence of other autoimmune disease and was diagnosed to have primary Sjogren syndrome.

Discussion

In elderly patients with profound hypokalemia and paralysis, gastrointestinal disorders, malnutrition with low [K.sup.+] intake, and medication interactions are three commonly encountered etiologies. Generating a rapid differential diagnosis and proper treatment is still a challenge to physicians. The assessment of renal [K.sup.+] excretion in response to hypokalemia and measurement of blood acid-base status may aid in the differential diagnosis. In general, HP can be simply divided into two groups: hypokalemic periodic paralysis caused by a shift of [K.sup.+] into cells, which is associated with low urine [K.sup.+] excretion and relatively normal acid-base status, and nonhypokalemic periodic paralysis caused by large [K.sup.+] deficit, which is usually associated with hyperchloremic metabolic acidosis or hypochloremic metabolic alkalosis. (5)

In these two patients, hypokalemia with low urine [K.sup.+] concentration may be mistakenly interpreted as low [K.sup.+] intake or excessive gastroenteric [K.sup.+] loss. However, TTKG, an index of renal [K.sup.+] excretion, was high and indicative of renal [K.sup.+] wasting. Normal plasma anion gap metabolic acidosis, along with low urinary excretion of N[H.sub.4.sup.+] reflected by a positive UAG and alkaline urine, pointed to the diagnosis of dRTA, which was established by the findings of normal F[E.sub.HCO3.sup.-] and low U-B PC[O.sub.2] during NaHC[O.sub.3] loading test. Further immunologic workup and salivary scintigraphy in both cases indicated a possible diagnosis of Sjogren syndrome as a cause of dRTA, although neither had any subjective sicca syndrome. Extensive workup differentiated the primary SS from other rheumatic or systemic disorders. During follow-up, they did have sicca syndrome without evidence of other autoimmune disease and met the criteria of primary Sjogren syndrome.

In contrast to the typical middle-aged female population, the subjective symptoms of SS, like sicca syndrome and musculoskeletal discomfort, might be very mild and easily neglected in the elderly group. HP is a striking manifestation and may precede sicca syndrome from 3 months to 4 years in patients with a final diagnosis of SS. (6,7) In those previously reported cases with initial presentation of HP, the age ranged from 14 to 54 years old and all were females. In these two patients, renal involvement with dRTA and HP unveiled the presence of SS and preceded the appearance of typical sicca syndrome by 5 months to 1 year. Both patients were elderly and male. One previous study also claimed that subjective sicca syndrome may develop 1 to 48 (mean, 15) years after the primary presentation of dRTA and/or urolithiasis in patients with possible SS who had a positive anti-Ro antibody and typical chronic tubulointerstitial nephritis. (8) Taken together, this suggests that dRTA associated with a positive anti-Ro antibody, typical chronic tubulointerstitial nephritis and the exclusion of other autoimmune disorders may be the forme fruste of primary Sjogren syndrome, even without subjective sicca syndrome.

Distal renal tubular acidosis is a disease of tubular dysfunction with impaired urine [H.sup.+] excretion in the intercalated cells of the distal collecting tubule and characterized by hyperchloremic metabolic acidosis, low urinary N[H.sub.4.sup.+], and alkaline urine (pH > 5.5). Causes of dRTA are either hereditary or acquired. Among the acquired dRTA, SS is the most common cause. In fact, the kidney is by far one of the most common extraglandular involvement sites, and dRTA is common if renal involvement occurs in SS. Distal renal tubular acidosis, a marker of more severe renal involvement in SS, has been reported to occur in almost 25 to 40% of patients with SS. (9,10) However, the exact mechanism of dRTA in SS remains elusive. Previous reports suggest an autoimmune process characterized by hyperglobulinemia and non-organ-specific autoantibodies. (11) Recent studies found that specific immune-mediated damage to the intercalated cells may be important in the pathogenesis of dRTA in SS. (12) It appears that patients with extensive immunologic and histologic findings seem to be susceptible to dRTA. Therefore, steroids should be used as early as possible in this severe SS-related tubulointerstitial nephritis. (10) Accordingly, we gave our patients steroid treatment, which effectively controlled the extraglandular involvement.

Hypokalemia is the most common electrolyte abnormality in patients with dRTA. The mechanisms of dRTA-induced hypokalemia include decreased distal tubular [Na.sup.+] delivery, secondary hyperaldosteronism, defective [H.sup.+]-[K.sup.+] ATPase, and bicarbonaturia. (13) Accordingly, hypokalemia in dRTA should be corrected before alkali therapy because alkali therapy might aggravate hypokalemia by enhancing a shift of [K.sup.+] into cells and bicarbonaturia. Furthermore, control of the underlying renal involvement of SS is essential. These two patients received prednisolone and achieved satisfactory control of their disease without renal function deterioration or other extraglandular involvement.

Drug-induced HP is also easily encountered in the elderly and deserves to be mentioned. Diuretics are the most common medications, due to the increased prevalence of hypertension and edematous status with age. Long-term use or large doses of diuretics for different purposes can easily induce severe iatrogenic hypokalemia in elderly patients susceptible to paralysis. (14) Likewise, licorice-containing substances and other medications are also possible hidden causes of hypokalemic paralysis. (15) A comprehensive review of medications and assessment of blood acid-base status can expedite the exclusion of the drug-induced HP. Both diuretics and licorice-induced HP are usually associated with metabolic alkalosis, in contrast to the metabolic acidosis seen in our two cases.

Conclusion

Renal involvement presented with HP may precede the typical sicca syndrome and unveil Sjogren syndrome regardless of age and sex. The measurement of the urine [K.sup.+] excretion rate and blood acid-base status could provide a rapid differentiation of HP. Early recognition and prompt therapy for Sjogren syndrome (or possible SS), especially with steroids, not only terminates potentially life-threatening paralysis but also prevents further complications related to Sjogren syndrome.

References

1. Lin SH, Davids MR, Halperin ML. Hypokalaemia and paralysis. QJM 2003;96:161-169.

2. Pokorny G, Sonkodi S, Ivanyi B, et al. Renal involvement in patients with primary Sjogren's syndrome. Scand J Rheumatol 1989;18:231-234.

3. al-Jubouri MA, Jones S, Macmillan R, et al. Hypokalaemic paralysis revealing Sjogren's syndrome in an elderly man. J Clin Pathol 1999;52:157-158.

4. Vitali C, Bombardieri S, Jonsson R, et al. Classification criteria for Sjogren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 2002;61:554-558.

5. Lin SH, Lin YF, Chen DT, et al. Laboratory tests to determine the cause of hypokalemia and paralysis. Arch Intern Med 2004;164:1561-1566.

6. Pun KK, Wong CK, Tsui EY, et al. Hypokalemic periodic paralysis due to the Sjogren syndrome in Chinese patients. Ann Intern Med 1989;110:405-406.

7. Shioji R, Furuyama T, Onodera S, et al. Sjogren's syndrome and renal tubular acidosis. Am J Med 1970;48:456-463.

8. Eriksson P, Denneberg T, Enestrom S, et al. Urolithiasis and distal renal tubular acidosis preceding primary Sjogren's syndrome: a retrospective study 5-53 years after the presentation of urolithiasis. J Intern Med 1996;239:483-488.

9. Pertovaara M, Korpela M, Kouri T, et al. The occurrence of renal involvement in primary Sjogren's syndrome: a study of 78 patients. Rheumatology 1999;38:1113-1120.

10. Siamopoulos KC, Mavridis AK, Elisaf M, et al. Kidney involvement in primary Sjogren's syndrome. Scand J Rheumatol 1986;61:156-160.

11. Konishi K, Hayashi M, Saruta T. Renal tubular acidosis with autoantibody directed to renal collecting-duct cells. N Engl J Med 1994;331:1593-1594.

12. DeFranco PE, Haragsim L, Schwartz PG, et al. Absence of vacuolar [H.sup.+]-ATPase pump in the collecting duct of a patient with hypokalemic distal renal tubular acidosis and Sjogren's syndrome. J Am Soc Nephrol 1995;6:295-301.

13. Lin SH, Cheema-Dhadli S, Gowrishankar M, et al. Control of excretion of potassium lessons from studies during prolonged total fasting in human subjects. Am J Physiol 1997;273:F796-F800.

14. Shintani S, Shiigai T, Tsukagoshi H. Marked hypokalemic rhabdomyolysis with myoglobinuria due to diuretic treatment. Eur Neurol 1991;31:396-398.

15. Cheng CJ, Chen YH, Chau T, et al. A hidden cause of hypokalemic paralysis in a patient with prostate cancer. Support Care Cancer 2004;12:810-812.

Chih-Jen Cheng, MD, Jainn-Shiun Chiu, MD, Chun-Chi Chen, MD, and Shih-Hua Lin, MD

From the Division of Nephrology and the Division of Rheumatology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.

Reprint requests to Shih-Hua Lin, MD, Division of Nephrology, Department of Medicine, Tri-Service General Hospital, Number 325, Section 2, Cheng-Kung Road, Neihu 114, Taipei, Taiwan. Email: [e-mail]

Accepted July 19, 2005.

RELATED ARTICLE: Key Points

* Hypokalemic paralysis is a less recognized but potentially reversible electrolyte disorder seen in the elderly.

* Hypokalemic paralysis caused by distal renal tubular acidosis may unveil Sjogren syndrome in elderly patients, even without initial typical sicca syndrome.

* Although Sjogren syndrome usually affects middle-aged females, it can affect elderly males.

* Distal renal tubular acidosis, a marker of more severe renal (extraglandular) involvement, can predate the typical exocrine involvement in Sjogren syndrome.

* The optimal treatment for Sjogren syndrome associated with distal renal tubular acidosis-related hypokalemic paralysis not only corrects the acidosis and hypokalemia but also controls the underlying renal involvement.

Table. Biochemical studies in two elderly males with Sjogren syndrome
presenting with hypokalemic paralysis (a)

                              Normal range  Case 1     Case 2

Age (years old)/sex                           74/male    78/male
Nephrocalcinosis                             Yes       No
Serum
  [Na.sup.+] (mmol/L)         136-145        143        138
  [K.sup.+] (mmol/L)            3.5-5.0        1.4        1.8
  [Cl.sup.-] (mmol/L)          98-107        117        113
  HC[O.sub.3.sup.-] (mmol/L)   22-24          17.8       16.1
  pH                            7.35-7.45      7.33       7.32
  BUN (mg/dL)                   7-20          13.5       15
  Cr (mg/dL)                    0.5-1          1.0        0.9
  Anion gap (mEq/L)             8-10           8.2        8.9
  IgG (mg/dL)                 751-1560      1630       2145
  IgA (mg/dL)                  82-453        420        236
  IgM (mg/dL)                  46-304        150        210
  ANA                          <1:40           1:1280     1:640
  RF (IU/mL)                    0-20         272        142
  C3 (mg/dL)                   79-152         75.4       78.2
  C4 (mg/dL)                   16-38          11.8       14.5
  Anti-Ro antibody              -              +          +
  Anti-La antibody              -              -          -
Urine
  [Na.sup.+] (mmol/L)                         66.0       87
  [K.sup.+] (mmol/L)                          12.8       14.6
  [Cl.sup.-] (mmol/L)                         65.0       84.0
  Cr (mg/dL)                                  45.2       56.8
  TTKG                                         9.1        7.1
  pH                                           7.6        7.5
  UAG (mEq/L)                                 13.8       17.6
  Protein (mg/d)                             620        550

(a) ANA, anti-nuclear antibody; Cr, creatinine; RF, rheumatoid factor;
TTKG, transtubular potassium concentration gradient: (urine [K.sup.+]/
plasma [K.sup.+])/(urine osmolality/plasma osmolality); UAG, urine anion
gap: Urine [Na.sup.+] + [K.sup.+] - [Cl.sup.-]; +, positive; -,
negative.