Severe Hypokalemia Complicated by Acute Myopathy: Initial Manifestation of Primary Sjögren’s Syndrome-Associated Renal Tubular Acidosis

Background

Hypokalemia is one of the most common problems seen in the Emergency Department (ED) and has been associated with increased mortality in patients with various conditions such as diabetes, chronic kidney disease, myocardial infarction, and heart failure [1–3]. Severe hypokalemia, defined as serum potassium less than or equal to 2.5 mmol/L, accounts for 0.4~1% of ED admissions, and approximately 49~80% are characterized primarily by weakness and muscle pain [2–4]. The etiology of severe hypokalemia in patients is numerous and complex, and failure to restore the concentration of serum potassium ion in a timely, effective, and standardized manner is highly likely to result in life-threatening complications such as malignant arrhythmias, muscle paralysis, and respiratory failure [2,4,5]. Therefore, treatment and identification of the etiology of this potentially fatal acute critical illness is urgent.

Acute myopathy, defined by a serum creatine kinase (CK) level 1.5 times higher than normal and characterized by pain, tenderness, swelling, and/or weakness, is an inflammation of the muscles, caused primarily by various neuromuscular diseases [6,7]. Despite evidence of acute myopathy in the form of elevated muscle enzymes, such as CK, glutamic oxalacetic transaminase (AST), glutamic-pyruvic transaminase (ALT), and lactate dehydrogenase, muscle biopsy may not be warranted due to its invasive nature or the transient and benign nature of some acute myopathy, especially if there is a clear etiology and typical presentation, while other investigations such as electromyography (EMG) may be helpful in not only confirming muscle disease as the cause of weakness but also in diagnosing the etiology of acute myopathy [7,8]. Although hypokalemia, especially severe hypokalemia, is not a common etiology of acute myopathy, there is some evidence, including EMG and muscle biopsy, that severe hypokalemia can directly cause acute myopathy [7,9].

The burden of autoimmune diseases increases over time, at different rates in different diseases, and the relationships among autoimmune diseases are consistent with a common etiology or causative agent, particularly among connective tissue diseases and endocrine diseases [10,11]. Sjögren’s syndrome (SS) is an autoimmune disease with diverse clinical manifestations, mainly lymphocyte proliferation and infiltration, and progressive exocrine gland injury, mostly accompanied by weakness and pain and other clinical manifestations [12]. The incidence of this disease is approximately 12.3/1000, and approximately 2~5% of patients have complications of lymphoma [10–13]. It is extremely rare to report SS with renal tubular acidosis (RTA) and hypokalemia, especially with acute myopathy as the initial clinical manifestation, although approximately 30% of SS patients are associated with renal interstitial injury [11,12,14–16].

Here, we report a 35-year-old woman with a definitive diagnosis of primary SS (pSS) and SS-associated RTA (SS-RTA). We hope that emergency physicians will pay greater attention to these diseases and complete the diagnostic and therapeutic process in a timely, effective, and standardized manner.

Case Report

A 35-year-old woman presented to our Emergency Department (ED) with a 20-day history of weakness in both upper limbs and a 1-week history of weakness in both lower limbs. One week ago, while traveling, the patient developed weakness in both lower limbs and pain in the right medial thigh and was unable to walk. Physical examination mainly revealed a large rash on the face, mainly on both cheeks (Figure 1), and the degree of muscle strength was level 3 according to the Lovett scale. There were no signs or symptoms of cranial nerve palsy, respiratory depression, and sensory degeneration. Her emergency laboratory tests for major abnormalities showed that the serum potassium concentration was 1.7 mmol/L (3.5~5.5 mmol/L, ↓), CK was 7586 U/L (40~200 U/L, ↑), CK-myocardial band (MB) was 310 U/L (0~18 U/L, ↑), AST was 161 U/L (0~40 U/L, ↑), and ALT was 113 U/L (0~40 U/L, ↑).

The patient had a long travel history before the onset of the disease; weakness and muscle pain were the main clinical manifestations, and CK was more than 5 times normal. At first, we diagnosed the patient with acute myopathy (rhabdomyolysis), and immediately started treatment measures such as intravenous fluid supplementation and serum potassium concentration supplementation [17,18]. Inconsistent with typical acute myopathy, the EMG results showed mixed-source damage to the right deltoid and right tibialis anterior muscles. Routine urinalysis revealed a pH of 7.50, which was not consistent with the routine characteristics of acute myopathy, in particular rhabdomyolysis [7,8,17].

Since the patient was a young woman and the major abnormal findings described above, including clinical presentation, physical examination, laboratory tests, and EMG, further laboratory tests were done to evaluate for autoimmune diseases such as lupus, autoimmune hepatitis, and diseases causing liver injury such as hepatitis [19, 20]. Abnormal results included significantly elevated concentrations of immunoglobulin (Ig) G (1840.00 mg/dL) and rheumatoid factor (RF) (66.50 IU/mL), and anti-nuclear, anti- Anti-SS-related antigen A (SSA), and anti-Ro-52 were all positive. Following the guidelines for autoimmune diseases, especially SS, the exocrine glands were examined and revealed diffuse lesions in bilateral submandibular glands (Figure 2), a positive Schirmer’s test for the dry eye test, and a biopsy of the labial glands showing the intact lobular structure, dilatation and congestion of vessels around the ducts in some glands, perivascular inflammation with lymphocyte infiltration, and lymphoid follicular formation (Figure 3). The diagnosis and management of primary SS (pSS) in this patient was established by topical and systemic treatment according to the EULAR 2020 recommendations for the management of SS – she mainly received oral treatment with 40 mg of methylprednisolone daily, depending on the patient’s weight [12].

Arterial blood gas analysis revealed a hyperchloremic metabolic acidosis, a marked increase in 24-hour urine potassium (202 mmol), alkaline urine on routine urine tests, and the enzyme spectrogram of N-hexanoyl-BD glucose (NAG) analysis revealed a significant increase in NAG (25.7 U/gcr) and NAG-A (22.1 U/gcr), indicating renal interstitial injury [21]. We concluded that the hypokalemia of the patient was due to renal tubular acidosis (RTA) and treated the patient with oral potassium citrate (1.46 g/dose, 3 times a day) to restore the serum potassium ion concentration [21,22]. The most likely cause of the RTA was a renal interstitial injury that was caused by the pSS [23]. We further performed a myo-zymogram examination, and the results revealed an anti-SSA/Ro-52KD antibody concentration of 70 Au (++), so in combination with the results of the EMG, the most likely cause of acute myopathy was hypokalemia caused by pSS [12,18]. The patient had an abnormal liver function, but laboratory tests related to liver injuries, such as autoimmune hepatitis and viral hepatitis, were normal, so we considered the abnormal liver function of the patient as a clinical manifestation of pSS, which could even be related to acute myopathy [12]. Since she refused to undergo further kidney, liver, and muscle biopsies, it was not pathologically clear whether RTA, muscle damage, and abnormal liver function were associated with pSS.

Discussion

SS is an autoimmune disease that primarily affects the exocrine glands and presents as a chronic infiltration of lymphocytes, including both primary and secondary SS [12]. The majority of patients with autoimmune diseases are females. Since we did not find sufficient evidence in this patient to support a diagnosis of other autoimmune diseases such as systemic lupus erythematosus, she was ultimately diagnosed with pSS according to guidelines for the management of SS [10–12,19,24]. In addition to the typical clinical manifestations of dry mouth and eye with the function of salivary and lacrimal glands impaired, approximately 50% of patients with SS present multi-system damage due to the infiltration of lymphocytes in the lung, liver, kidney, skin, blood vessels, and nervous system [10,12,14]. The infiltration of ductal and perivascular lymphocytes in salivary and lacrimal glands is the main histological feature of SS. Further infiltration of inflammation leads to the complete destruction of the acinus, loss of gland secretion function, and the eventual development of B-cell lymphoma [22]. Early formulation of intervention therapy and suppression or termination of abnormal immune response in patients is the key to preventing the destruction of exocrine glands such as salivary glands and lacrimal glands, protecting the functions of various organs, and reducing the risk of complicated malignant lymphoma [12]. Clinical manifestations and laboratory examination are the main basis for the diagnosis of SS [12,23]. According to the diagnostic guidelines for SS, despite the patient’s atypical clinical symptoms, the total score was 7, consistent with the pSS diagnosis [14].

The kidney is one of the common extra-glandular organs involved in SS, with an involvement rate of 0.3–33.5%, most of which occur 2~7 years after the diagnosis of SS [22–24]. Pathophysiological manifestations of renal injury are mainly interstitial nephritis caused by infiltration of lymphocytes into renal tubular epithelial cells and membranous or membranous proliferative glomerulonephritis caused by immune complex precipitation [22]. The onset of kidney injury has hidden clinical symptoms that are not typical. Most of them are abnormal in laboratory examination (eg, NAG enzyme, b2 microglobulin, urine protein, urine pH), or lymphocyte infiltration is confirmed by renal puncture biopsy, and only a few have obvious clinical symptoms [22,24]. This patient was positive for NAG enzyme, and the preliminary consideration was that there were fewer symptoms of dry eye and dry mouth in SS patients with kidney injury compared with SS patients alone, which was consistent with this patient [23]. The etiology of RTA includes primary and secondary causes, and the secondary causes are the main ones. The most common secondary disease is SS, and distal renal tubule acidosis (dRTA) is the most common RTA caused by SS, while the primary cause is a mostly autosomal dominant genetic disease. Clinical manifestations of dRTA mainly include metabolic acidosis, abnormal alkaline urine, hypokalemia, osteoporosis, and osteocalcinosis [23]. In this patient with severe hypokalemia, hyperchloric metabolic acidosis, increased urinary potassium, and repeated urine routine showed alkaline pH, which was consistent with dRTA manifestations.

This patient also had acute myopathy, which is commonly seen in various neuromuscular diseases and is rarely reported to be caused by hypokalemia. A low serum potassium concentration of 2.0 mmol/L will lead to changes in myosinology, and the decrease of extracellular potassium concentration will lead to intracellular potassium transfer to extracellular, which will further imbalance the sodium-potassium pump and lead to cell edema and degeneration. Severe hypokalemia causes metabolic disorders of muscle cells, leading to the accumulation of a large number of free fatty acids in the cells, promoting the increase of membrane permeability and the release of intracellular CK into the blood [2,4,5,14]. The patient’s serum potassium ion concentration was as low as 1.47 mmol/L, and the EMG of the right deltoid muscle and the right tibia anterior muscle showed mixed-source lesions, consistent with the manifestations of edema, degeneration, and injury of the muscle cells after severe hypokalemia.

Conclusions

The final diagnosis consisted of pSS and SS-RTA. The patient’s condition improved following treatment with methylprednisolone and potassium citrate. Severe hypokalemia is a serious life-threatening medical emergency, and the differential diagnosis is broad. We should improve the understanding of its relationship with SS and SS-RTA, especially in a young woman with acute myopathy.