Primary Sjogren’s syndrome presenting as hypokalaemic periodic paralysis and acute pancreatitis

Summary

Renal tubular acidosis is a well-known consequence of primary Sjogren’s syndrome (pSS), but a rare manifestation similar to acute pancreatitis in pSS. Here, we discuss the case of a woman in her 50s, who presented to a tertiary care hospital with recurrent episodes of sudden-onset weakness in all four limbs, recurrent vomiting and epigastric pain. She had non-anion gap metabolic acidosis with hypokalaemia and was diagnosed with pSS with hypokalaemic periodic paralysis. She was also diagnosed with acute pancreatitis based on elevated amylase and lipase levels and CT findings. The article highlights the diverse spectrum of clinical manifestations of pSS, including renal and pancreatic involvements, which can be rare consequences of the disease.

Background

Primary Sjogren’s syndrome (pSS) is a chronic autoimmune disease that affects the exocrine glands, mainly the salivary and lacrimal glands, resulting in sicca symptoms. Systemic symptoms and extraglandular manifestations occur in about one-third and 15% of pSS patients, respectively.¹ Among the extraglandular manifestations, renal involvement is not uncommon, with tubulointerstitial nephritis (TIN) and glomerulonephritis (GN) being the most common kidney diseases.² Although distal renal tubular acidosis (RTA) is a well-known consequence of autoimmune diseases, including SS, it is considered a rare manifestation of pSS.³ Additionally, pancreatic involvement, including pancreatitis, is another extraglandular manifestation that, while less common, can occur in pSS patients, contributing to the complexity and multisystemic nature of the disease. Managing these diverse manifestations requires a comprehensive, multidisciplinary approach to care.

In this article, we present a case of pSS presenting with hypokalaemic periodic paralysis due to distal RTA and abdominal pain due to acute pancreatitis.

Case presentation

A woman in her 50s, who worked on a family-owned farm in Northern India without any substance use or prior known comorbidities, presented to the emergency department of a tertiary care hospital with a sudden onset of weakness in her bilateral lower limbs that progressed to both upper limbs over a few hours. She described a sensation of cramping and discomfort during the episodes, which typically lasted for several hours. In the next hour, she developed recurrent vomiting with severe epigastric pain that radiated to her back, which resolves by bending forward. Over the last year, she had one similar weakness episode and was hospitalised at a local health centre, where she was found to have profound hypokalaemia that improved with an infusion of potassium chloride. Additionally, she reported joint pain and stiffness that affected her mobility and quality of life. She also reported a history of dry eyes with difficulty in vision and dry mouth with a burning sensation and difficulty swallowing for the last 5 years.

On examination, the patient was conscious and oriented to time, place and person. Her respiratory rate was 22 cycles per minute, and her blood pressure and heart rate were within normal limits. In neurological examination, she had hypotonia in all four limbs with neck and truncal weakness. Power in bilateral upper and lower limbs was 1/5 on the Medical Research Council grading scale. Her reflexes were normal, and there was no evidence of muscle atrophy or fasciculations. The sensory system and cranial nerves were normal. In the abdominal examination, she had epigastric tenderness without any evidence of fluid or organomegaly. Other system examinations were unremarkable including lack of any evidence of parotid swelling, dental caries, corneal ulceration, joint swelling or tenderness.

Investigations

The initial laboratory investigations revealed anaemia of chronic disease, raised amylase and lipase levels, a low serum potassium and bicarbonate levels with arterial blood gas analysis showing hyperchloraemic non-anion gap metabolic acidosis (table 1). The urine pH was >5.5. No blood or protein was detected in the urine. A positive urine anion gap of 24 and hypercalciuria confirmed RTA type 1 (due to the presence of hypokalaemia, hypercalciuria, non-acidic urinary pH and normal anion gap metabolic acidosis). Schirmer’s test done was suggestive of severely dry eyes, measuring 0 mm in bilateral eyes after 5 min while unstimulated salivary flow was less than 0.1 mL/min. Contrast-enhanced CT abdomen confirmed acute pancreatitis but without any cholelithiasis, choledocholithiasis, nephrocalcinosis or nephrolithiasis.

Table 1. Basic and advanced investigations, performed during evaluation of the case.

Investigations	Reference range (adults)	At admission
Haemoglobin (g/dL)	13.5–17.5	11.2
White cell count (x10∧9/L)	4.5–11	13.3
Platelets (x10∧9/L)	150–400	64
Aspartate aminotransferase (U/L)	5–40	45
Alanine aminotransferase (U/L)	5–45	18
Total bilirubin (mg/dL)	0.2–1.1	0.99
Direct bilirubin (mg/dL)	<0.20	0.22
Alkaline phosphatase (U/L)	<240	147
Serum total protein (g/dL)	6.4–8.1	7.6
Serum albumin (g/dL)	3.2–4.6	3.2
Sodium (mmol/L)	135–145	143
Potassium (mmol/L)	3.4–5.0	2.1
Chloride (mmol/L)	100–108	110
Arterial bicarbonate (mmol/L)	22–29	17
Arterial pH	7.35–7.45	7.21
Urea nitrogen (mg/dL)	8–25	10
Creatinine (mg/dL)	0.60–1.50	0.38
Glucose (mg/dL)	70–110	94
Lactate dehydrogenase	<8	154
Amylase	30–110 U/L	1120
Lipase	0–160 U/L	980
Erythrocyte sedimentation rate	Up to 30	35 mm/1 hour
C reactive protein	Up to 6.0 mg/dL	15.87
Urine pH	4.5–8.0	7.0
Urine potassium (mmol/L)	25–125	18.4
Urine chloride (mmol/L)	110–250	68
Urine sodium (mmol/L)	20–220	74
Urine calcium (mmol/day)	2.5–7.5	12.1
Viral markers (Hepatitis B surface antigen, anti-Human Immunodeficiency Virus and anti-Hepatitis C virus)	–	Negative

A minor salivary gland biopsy revealed the presence of lymphocytic infiltration with a focus score of 2 (figure 1A,B). Moreover, the indirect immunofluorescence test on HEP-2 cells detected 4+positive antinuclear antigen with a titre of 1:640 and a speckled pattern. The line immunoassay for extractable nuclear antigen tested was positive for IgG anti-SSA (Ro) antibodies. According to the American College of Rheumatology-European League Against Rheumatism 2017 classification criteria, she was diagnosed with pSS with a total score of 8, based on the following weighted items:

Figure 1. Histopathology images of minor salivary gland biopsy. H&E-stained section at ×100 (A) and ×200 (B) showing a typical focal lymphocytic infiltrates in the periductal and perivascular distribution surrounded by normal acinar tissue with focus score of 2.

• Labial salivary gland biopsy: The presence of focal lymphocytic sialadenitis with a focus score of ≥1 foci/4 mm² (3 points).

• Anti-SSA/Ro antibodies: Positive serology for anti-SSA (Ro) antibodies (3 points).

• Ocular Staining Score: An ocular staining score of ≥5 (or van Bijsterveld score of ≥4) in at least one eye (1 point).

• Schirmer test: Schirmer’s test result of ≤5 mm/5 min in at least one eye (1 point).

• Unstimulated whole saliva flow rate: Unstimulated salivary flow rate of ≤0.1 mL/min (1 point).

Differential diagnosis

Considering the recurrent history of hypokalaemic paralysis, the diagnosis was straightforward with type 1 RTA. Advanced chronic kidney disease, diabetic ketoacidosis, gastrointestinal losses, aldosterone deficiency or resistance, drugs or toxins and autoimmune diseases such as lupus nephritis or autoimmune interstitial nephritis were considered differentials in this case. However, the constellation of type 1 RTA, pancreatitis, dry eyes and dry mouth led to the clinical diagnosis of pSS.

Treatment

She was treated with intravenous potassium chloride through central venous line due to intolerable oral potassium citrate along with sodium bicarbonate. Her weakness started improving after the normalisation of serum potassium levels. With supportive therapy, abdominal pain also recovered.

Outcome and follow-up

She was discharged with stable vitals with prescription of potassium citrate 20 mEq orally three times daily, tapered over 2 months and is being followed up regularly for the treatment of pSS in the rheumatology clinic with disease-modifying antirheumatic drug—hydroxychloroquine and azathioprine.

Discussion

The present case presented with classic sicca symptoms alongside hypokalaemic periodic paralysis and pancreatitis and was confirmed to be pSS. This is a chronic autoimmune condition marked by lymphocytic infiltration of the exocrine glands, primarily the salivary and lacrimal glands, which causes sicca symptoms. Systemic symptoms are present in about one-third of SS patients. Extraglandular manifestations, which impact the lungs, skin, joints, neurological system and kidneys, are present in 15% of pSS patients.¹ These manifestations add to the disease’s already significant morbidity and mortality rates.

Renal manifestations occur in 5% of patients with primary pSS, especially TIN and GN are the two most frequent kidney diseases.² Although studies have shown that a greater proportion of adult patients experience TIN-related distal tubular acidification abnormalities, distal RTA can be a rare consequence of pSS.³ Goroshi et al published one case series, with 50% of individuals having RTA and one-third meeting the criteria for the diagnosis of pSS.⁴ At the time of presentation, only 8% of individuals experienced sicca symptoms. After serology testing, 63% of patients with no indications and symptoms of exocrine gland involvement were diagnosed with pSS. Anti-Ro and anti-La antibodies were found in all cases while other antinuclear antibodies were not. Lip biopsy histopathology revealed mild salivary gland inflammation in all individuals. Schirmer’s test was positive in two cases (less than 5 mm).

Type 1 RTA is caused by a decrease in net H+secretion in the distal nephron and prevents urine acidification, reducing titratable acid and urinary ammonia excretion. A diagnosis can be made by observing the presence of normal anion-gap metabolic acidosis and a positive urine anion gap. Before genetic tests were introduced into clinical practice, some acid load tests such as sodium bicarbonate load, ammonium chloride load or the furosemide/fludrocortisone test were used to confirm primary type 1 RTA. For acquired cases, clinical diagnosis is sufficient as treatment of aetiology completely cures the entity.⁵ Hypokalaemia is caused by urinary potassium losses and severe hypokalaemia (<2.5 mmol/L) as in this patient can cause muscular weakness. While weakness caused by subsequent hypokalaemic paralysis is usually completely reversible, weakness caused by the chronic myopathy associated with periodic paralysis is typically persistent and unresponsive to treatment. In some patients, modest residual weakness may be observed between paralytic episodes.⁶ However, in the present case, there was a complete recovery of weakness after resolution of hypokalaemia.

While the pancreas is a gland that is quite similar to the salivary glands, clinical pancreatic involvement is one of the rarest manifestations of SS. There have been few studies in this field, and most of them were conducted more than two decades ago, with varied findings due to various methods and a limited number of patients involved.⁷ The connection between pSS and autoimmune pancreatitis is well established, although its prevalence is uncertain as case reports comprise the majority of scientific literature. Additionally, there are limited data on the incidence of chronic pancreatitis in the Indian population. Ramos-Casals et al reported a 0.5% occurrence of acute pancreatitis of any cause in their large series of pSS patients (1010 patients).⁸ Meanwhile, a cohort study by Chang et al found that patients with pSS had a higher risk of acute pancreatitis, with a 48% greater hazard in the pSS-affected group compared with the non-pSS population.⁹ In terms of the timing of when both autoimmune pancreatitis and pSS present, in several cases reported in the scientific literature, the diagnosis of pSS was made after the diagnosis of the gastrointestinal autoimmune pathology. However, it is unclear whether the patients had prior sicca symptoms as they were not intentionally evaluated for them. Other reports have described the simultaneous occurrence of both autoimmune pathologies. In the present case, sicca symptoms were there prior to pancreatitis.

Although the precise cause of the increased risk of pancreatitis in pSS remains unclear, postmortem analyses of individuals who had no previous pancreatic problems have revealed structural changes in the pancreas, including chronic pancreatitis, atrophy, replacement of pancreatic tissue with vascular connective tissue and lymphocytic infiltration. Since the pancreas shares similarities with other exocrine glands like the salivary gland, biliary duct and distal renal tubule, scientists have investigated the presence of antibodies against ductal cell antigens in patients with autoimmune chronic pancreatitis, pSS and both diseases.¹⁰

The primary approach for managing these patients continues to be symptomatic treatment. The present patient had significant symptom improvement after receiving potassium replacement therapy and has since been consistently taking oral potassium and bicarbonate supplements.¹¹ It is crucial to emphasise the importance of ongoing monitoring of renal function tests to detect any possible deterioration.

Learning points.

• Physicians should consider primary Sjogren’s syndrome (pSS) as a differential diagnosis in patients who present with hypokalaemic periodic paralysis, especially when associated with normal anion gap metabolic acidosis.

• Early recognition and management with lifelong potassium supplementation is enough to prevent further episodes of hypokalaemic paralysis.

• Like any other exocrine glands, pSS can involve the pancreas and present as pancreatitis.