Multiple autoimmune syndrome revealed by nephrogenic diabetes insipidus and hypokalaemic paralysis

Introduction

Autoimmune diseases (ADs) are complex diseases that result from the interaction between genetic and environmental factors over time. They begin with the loss of immunological tolerance to self-antigens, forming a heterogeneous group of disorders resulting in a spectrum of syndromes that can target specific organs or cause systemic compromise. ¹ Three main features of ADs have been recognized. Firstly, ADs do not begin at the time of presentation but instead several years previously. ¹ They have a chronic nature but varying clinical pictures, including the presence of autoantibodies in asymptomatic subjects or complications as the main symptoms. Secondly, a patient who develops an AD has an increased risk (25%) of developing additional ADs. ² The ‘kaleidoscope or mosaic of autoimmunity’ denotes the coexistence of various ADs within one individual. ¹ Thirdly, some of the aetiological and pathophysiological mechanisms might be shared among ADs, which can be termed ‘autoimmune tautology’. ³

Herein, we describe and discuss a representative case reflecting the characteristics of ADs mentioned above. The patient was admitted with nephrogenic diabetes insipidus and hypokalaemic paralysis, but was finally diagnosed with multiple autoimmune syndrome (MAS) comprising Sjögren’s syndrome (SS), systemic lupus erythematosus (SLE) and autoimmune thyroid disease (AITD).

Case report

A 33-year-old female and mother of one child presented to the Endocrinology Department of the First Affiliated Hospital of Dalian Medical University with dry mouth, thirst, polydipsia and polyuria that had developed after parturition six years previously, in addition to periodic weakness of both lower limbs in the last two years. She denied polyphagia, weight gain, an abortion, or using drugs or tobacco. Clinical and laboratory data on presentation are shown in Table 1.

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Table 1

Clinical and laboratory data of the patient on presentation

Height (cm)	163
Body weight (kg)	50
Blood pressure (mmHg)	90/60
Pulse (beats per minute)	78
Body temperature (℃)	36.5
Daily water intake (ml)	4000–5000
24-hour urine output volume (ml)	5000–6500
Urinalysis
Protein	±
pH	7.0–7.5
Specific gravity	1.002–1.005	1.015–1.025
Osmolality (mOsm/kg H2O)	89	600–1000
Potassium (mmol/24 h)	83.2–89.1	<25
Haematology
White blood cells (×109/l)	3.8	3.69–9.6
Neutrophils (%)	39.7	50–70
Lymphocytes (%)	43.8	20–40
Monocytes (%)	13.4	3–10
Blood chemistry
Potassium (mmol/l)	2.72–2.9	3.5–5.2
Chloride (mmol/l)	109	96–108
Cystatin C (mg/l)	1.41	0–1.03
Creatinine (µmol/l)	84	35–71
Total protein (g/l)	106.5	60–90
Globin (g/l)	58	25–35
Triglyceride (mg/dl)	173	<150
High-density lipoprotein cholesterol (mg/dl)	36	>40
Serology
IgG (mg/dl)	2160	700–1600
IgA (mg/dl)	472	70–453
Rheumatoid factor (IU/ml)	195	0–20
Antinuclear antibody	1:1000+ (speckled)
Anti-dsDNA antibody (IU/ml)	44.28	<10
Anti-SS-A antibody/60 kD	+++
Anti-SS-A antibody/52 kD	+++
Thyroid-stimulating hormone (µIU/ml)	8.34	0.27–4.2
Free thyroxine (pmol/l)	11.95	12–22
Anti-thyroid peroxidase antibody (IU/ml)	>420	<34
Anti-thyroglobulin antibody (IU/ml)	202.6	<115
Angiotensin I (ng/ml/h)	7.7	0.56–2.8
Angiotensin II (pg/ml)	63.67	29–71.6
Aldosterone (decumbent position: pg/ml)	407.49	29.4–161.5

The glucose tolerance test excluded diabetes mellitus. Electrolyte analyses confirmed hypokalaemia, and her initial diagnosis was hypokalaemic paralysis. Urinalyses revealed the increased excretion of urinary potassium. Evaluation of the activity of the angiotensin-aldosterone system activity suggested the hypersecretion of angiotensin I and aldosterone. However, her blood pressure remained constant at ≈90/60 mmHg. Her low urine gravity and osmolality had little response to fluid deprivation and stimulation with exogenous vasopressin.

Magnetic resonance imaging (MRI) of the hypothalamic-pituitary region was normal. A diagnosis of nephrogenic diabetes insipidus was established. Although her urinary pH was 7.0, blood gas analyses did not suggest metabolic acidosis. The ammonium chloride loading test led to a diagnosis of incomplete renal tubular acidosis. Ultrasonography revealed a haemangioma in the right liver lobe (12 × 11 mm) and normal kidneys. The serum level of creatinine was elevated mildly with a creatinine clearance of 81.12 ml/min per 1.73 m².

Further inquiry and physical examination by a consultant nephrologist and consultant rheumatologist provided new clues to the diagnosis. Before pregnancy, she had suffered photosensitivity, hair loss, mouth ulcers, arthralgia in small and large joints, and episodic low-grade fevers. A facial rash was also observed. Haematology revealed a slightly increased percentage of lymphocytes and monocytes. Immunological investigations suggested that she was positive for rheumatoid factor as well as for antinuclear, anti-double-stranded DNA (anti-dsDNA) and anti-Ro (SSA) antibodies. Hyperglobulinaemia was further evidenced by elevation of the levels of immunoglobulin G (IgG) and IgA. Therefore, the patient already fulfilled the criteria of SLE according to the revised classification set by the American College of Rheumatology in 1997. The score for the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) was 12. Additionally, Schirmer’s test was abnormal (5 mm in five minutes) even though she did not complain of dry eyes. To investigate the xerostomia, a biopsy of the minor salivary glands demonstrated multifocal lymphocytic and plasmacytic infiltration into the mesenchyme. SS could be diagnosed following the criteria proposed by the American-European Consensus Group. Assessment of thyroid function showed raised levels of thyroid-stimulating hormone, suppressed levels of free thyroxine as well as high titres of anti-thyroglobulin and anti-thyroid peroxidase antibodies. Ultrasound examination revealed normal thyroid volume with diffuse morphological alterations, and solid nodules were noted on the right lobe and isthmic portion. A diagnosis of Hashimoto’s thyroiditis with hypothyroidism was confirmed, even though she did not complain of anorexia, lethargy or constipation. The final diagnosis was of MAS (SS-SLE-AITD). The patient was administered potassium and levothyroxine, and discharged on oral prednisone (30 mg/d).

Discussion

The patient described here presented with what appeared to be multiple endocrine and metabolic disorders, and could easily have been misdiagnosed. However, after diabetes mellitus, disorders of the hypophyseal portal system and hypernatraemia were excluded, nephrogenic diabetes insipidus and hypokalaemic paralysis were diagnosed.

The periodic weakness in this patient occurred four years after the onset of polydipsia and polyuria. We inferred that hypokalaemia resulted from the dilution of serum potassium by the excessive intake of water and increased loss of potassium from the urine over a long period. Hyperaldosteronaemia could explain the phenomenon of hypokalaemia and the hyperexcretion of urinary potassium. However, the low blood pressure and high activity of angiotensin I strongly suggested that the hyperaldosteronaemia was secondary to volume depletion after long-term polyuria, and not primary aldosteronism. The elevated level of creatinine in serum and reduced glomerular filtration rate were probably associated with the prolonged hypoperfusion of glomeruli as well as renal ischaemia.

Impaired excretion of potassium within tubules, decreased urinary concentrating ability and inability to acidify urine were highly suggestive of distal renal tubular dysfunction. Trace proteinuria and an absence of haematuria also suggested tubulointerstitial involvement, which were compatible with the renal complications associated with SS. Admittedly, it should have been differentiated further from predominant tubulointerstitial nephritis related to SLE ⁴ if a renal biopsy was performed.

A diagnosis of MAS was based on the simultaneous coexistence of SS, SLE and AITD. MAS was first described by Humbert and Dupond in 1988 as a syndrome comprising ≥3 well-defined ADs in a single patient. ³ MAS is classified into three groups (types 1–3) ² and our patient was in the range of type 3. The prevalence of MAS has been reported to be 4%–8% among patients with ADs. ⁵ A total of 55.6% of MAS cases involve SS, and the most prevalent MAS patterns are SS-AITD-SLE.^3,5 SS, AITD and SLE have been considered to be the ‘chaperones’ of ADs, ¹ but how these three entities ‘encountered’ each other in our case is not clear. It seems that SLE preceded SS but, being insidious, was overlooked until the prominent complications of SS occurred. The same scenario could have occurred in AITD.

MAS represents the best example of poly-immunity as well as the effect of a single genotype on diverse phenotypes. However, the aetiology of MAS is poorly understood. ⁶ In our case, symptoms appeared after pregnancy, which implied that an imbalance of female hormones might have important roles in the pathogenesis of MAS, or might act as a triggering factor for the acquisition of self-tolerance. Pregnancy might have some correlation with susceptibility to MAS. Thus, screening for antinuclear antibody and other specific autoantibodies before pregnancy in predisposed females could be necessary.

We noticed that MAS in our case had more prominent mucocutaneous, articular and tubulointerstitial involvements, whereas glomerulonephritis, neurological disorders, serositis and haematological suppression were not observed. The SLEDAI score was close to a severe flare, but we believe that the activity of this entity was not that severe and outcomes were relatively benign.^5,7 Raised percentages of blood lymphocytes and monocytes suggested cellular immunity-mediated pathophysiological mechanisms, and that low-dose glucocorticoids might be helpful.

The current case provides a useful educational opportunity for clinical physicians to recognize the complex polyautoimmune phenomena. It alerts one to bear in mind the interrelationship of autoimmune pathogenesis and extending the range of immunological screening tests, reinforcing the need for extra vigilance and monitoring for additional ADs in women that are predisposed to autoimmunity who present with multiple disorders.