Sean Lockwood, MD

A previously healthy 30-year-old woman presented to the emergency department with 2 weeks of weakness.

True muscle weakness must be distinguished from the more common causes of asthenia. Many systemic disorders produce fatigue, with resulting functional limitation that is often interpreted by patients as weakness. Initial history should focus on conditions producing fatigue, such as cardiopulmonary disease, anemia, connective tissue disease, depression or cachexia related to malignancy, infection, or other inflammatory states. Careful questioning may reveal evidence of dyspnea, poor exercise tolerance, or joint pain as an alternative to actual loss of muscle power. If true weakness is still suspected, attention should be focused on the pattern, onset, anatomic site, and progression of weakness. Muscle weakness is often characterized by difficulty with specific tasks, such as climbing stairs, rising from a chair, raising a hand, or using cutlery. The physical examination is critical in determining whether weakness is due to true loss of motor power. The differential diagnosis of weakness is broad and includes neurologic, infectious, endocrine, inflammatory, genetic, metabolic, and drug-induced etiologies.

She initially experienced 3 days of mild cramps and soreness in her thighs. She then developed weakness that began in her thighs and progressed to involve her lower legs and upper and lower arms. She had difficulty combing her hair. She required the use of her arms to get up from a chair. She grasped onto objects to aid in ambulation around the house. In addition, she described 1 year of moderate fatigue but no fever, weight loss, dyspnea, dysphagia, visual changes, paresthesias, bowel or bladder incontinence, back pain, or preceding gastrointestinal or respiratory illness. She had experienced diffuse intermittent hives, most prominent in her chest and upper arms, for the past several weeks.

History certainly supports true weakness but will need to be confirmed on examination. The distribution began as proximal but now appears diffuse. The presence of myalgia and cramping raises the possibility of noninflammatory myopathies, which are usually more insidious in onset. A severe electrolyte disturbance would be possible, based on the diffuse nature of weakness that was preceded by cramping. The distribution of weakness and lack of bowel or bladder incontinence is reassuring and suggests against a spinal cord disorder; however, a high index of suspicion must be maintained for myelopathy because delayed treatment might result in irreversible paralysis.

The patient’s course also includes hives. Common causes of hives include infections and allergic reactions to medications, foods, and insect stings. Urticaria may also result from systemic disorders, such as vasculitis, lupus, lymphoma, mastocytosis, and paraproteinemias, which can be associated with weakness and fatigue. Although severe weakness in combination with hives makes an infectious and allergic reaction less likely, we still seek to ascertain if the evolving chief complaints of weakness and hives are the result of a single unifying and evolving multisystem disorder or are distinct and unrelated processes.

Her past medical history included fibromyalgia, kidney stones, and gastroesophageal reflux disease. One week prior to presentation, she was prescribed prednisone 60 mg daily for the treatment of hives; the dose had been tapered to 40 mg at presentation, with mild improvement of hives. She recently started doxepin for fibromyalgia and insomnia. She lived at home with her husband and 8-year-old child. She worked as a clerk in a pest control office and denied any pesticide exposure. She denied tobacco, alcohol, or illicit drug use. Her family history included systemic lupus erythematosus (SLE) in her mother and maternal aunt.

Glucocorticoids are associated with myopathy; however, the weakness preceded steroid therapy. Thus, unless there was unknown exposure to high-dose steroid medication to treat recurrent episodes of urticaria earlier in her course, glucocorticoid-related myopathy is unlikely. Fibromyalgia might cause the perception of weakness from pain. However, the history of difficulty combing her hair and rising from a chair suggests actual loss of motor power. The side effects of her medications, such as newly started doxepin, must be reviewed. A family history of SLE raises concern for rheumatologic conditions; however, one might expect improvement with steroid therapy.

On physical examination, her temperature was 36.9 °C, blood pressure 126/93 mmHg, pulse 81 beats per minute, respiratory rate 16 breaths per minute, and oxygen saturation 100% on ambient air. Her cardiopulmonary examination was normal. Her abdomen was nontender and without hepatosplenomegaly. Her strength was 2 out of 5 in proximal and distal legs, bilaterally, and 4 out of 5 in proximal and distal upper extremities. She had normal muscle tone without fasciculations or atrophy. Her joints were without edema, erythema, or impaired range of motion. She had normal sensation to light touch in arms and legs. Her reflexes were 2+ in the patellar, Achilles, and brachioradialis tendons. She had no lymphadenopathy, mucosal ulcerations, or alopecia. A skin examination revealed smooth, slightly elevated, and faded pink wheals that were diffuse but most prominent in upper arms and chest.

Physical examination confirms the presence of true muscle weakness. The differential diagnosis is narrowed by several findings, both positive and negative, elicited in the examination. The diffuse nature of the weakness eliminates focal central nervous system lesions, such as stroke, intracranial mass lesions, or demyelinating white matter foci. Combining this finding with normal reflexes and history of preceding myalgias makes electrolyte-induced and inflammatory (eg, polymyositis) myopathies more likely. The normal deep tendon reflexes and the absence of a delayed relaxation phase lower the likelihood of hypothyroidism. 

Diseases originating from the neuromuscular junction, such as myasthenia gravis, may also present with weakness and normal reflexes, although this pattern of weakness would be atypical; myasthenia gravis classically presents with fatigable weakness and ocular findings of diplopia and/or ptosis. First-tier testing should include a complete blood count to evaluate for eosinophilia, comprehensive metabolic panel, and urinalysis for myoglobinuria, thyroid stimulating hormone, and muscle enzymes. 


Results of a complete blood count demonstrated a leukocyte count of 16.1 k/uL with 82% neutrophils, 13% lymphocytes, 5% monocytes, and 0% eosinophils. Hemoglobin was 13.2 g/dL, and platelet count 226 k/uL. Sodium was 136 mmol/L, potassium 1.5 mmol/L, chloride 115 mmol/L, bicarbonate 12 mmol/L, blood urea nitrogen 26 mg/dL, creatinine 1.0 mg/dL (baseline creatinine: 0.6), and glucose 102 mg/dL. Calcium was 9.4 mg/dL, magnesium 2.6 mg/dL, phosphorus 1.8 mg/dL, CK 501 U/L (normal: 40-230), and TSH 5.48 uIU/mL (normal: 0.5-4). Aspartate aminotransferase was 64 U/L, alanine aminotransferase 23 U/L, alkaline phosphatase 66 U/L, bilirubin 0.9 mg/dL, albumin 3.8 g/dL, and total protein 8.7 g/dL (normal: 6.2-7.8). Human immunodeficiency virus antibody screen was negative. An electrocardiogram revealed normal sinus rhythm, flattened T waves, and prominent U waves.

Potassium losses are classically categorized into 1 of 3 groups: renal losses, gastrointestinal losses, or transcellular shifts. Without a clear history of diuretic use, renal losses may not be apparent on history and examination. In contrast, gastrointestinal losses are almost always evidenced by a history of vomiting and/or diarrhea, with rare exceptions, including unreported laxative abuse or surreptitious vomiting. Transcellular potassium shifts can be seen in states of increased insulin or beta-adrenergic activity and alkalosis and result from both primary and secondary causes of hypokalemic periodic paralysis.

The presence of a reduced serum bicarbonate and elevated chloride concentration suggests a normal anion gap metabolic acidosis. Many conditions associated with normal anion gap metabolic acidosis are evident by history, such as diarrhea. In enigmatic cases such as this, it will be important to take a stepwise approach that includes an evaluation for urinary potassium losses and assessment of acid-base status. An unexplained normal anion gap metabolic acidosis combined with hypokalemia raises suspicion for a distal renal tubular acidosis (RTA). Additional testing to evaluate for a possible RTA should include the assessment of urinary electrolytes and urinary pH. The hypokalemia explains her weakness, but the etiology of such profound hypokalemia is not evident, nor is it clear how it relates to her hives.

The severity of the hypokalemia, combined with electrocardiogram changes, necessitates rapid intravenous potassium repletion, telemetry monitoring, and frequent serum potassium measurement. Treatment of her metabolic acidosis is more nuanced and depends upon both the severity of disturbance and the suspicion of whether the etiology is transcellular shift, potassium depletion, or both.

Urine studies demonstrated a urine specific gravity of 1.006 (normal: 1.001-1.030), urine pH was 6.5 (normal: 5-6.5), trace leukocyte esterase, negative nitrite, 30 mg/dL of protein (normal: <15), sodium 64 mmol/L (normal: 40-220), potassium 17 mmol/L (normal: 25-125), and chloride 71 mmol/L (normal: 110-250). Urine microscopy demonstrated 3 red blood cells per high power field (normal: 0-1), 4 white blood cells per high power field (normal: 0-4), 4+ bacteria per high power field, and no red blood cell casts. Urine protein-to-creatinine ratio was 1.6. C3 and C4 complement levels were 53 mg/dL (normal: 80-165) and 12 mg/dL (normal: 15-49), respectively. C-reactive protein was <0.5 (normal: 0-0.9), and erythrocyte sedimentation rate was 16 mm/hour (normal: 0-20).

A calculation of the urine anion gap (UAG; [urine sodium + urine potassium] – urine chloride) yields a UAG of 10 mq/L. A positive UAG, together with a nongap metabolic acidosis, should prompt the consideration of RTA. The normal renal response to acidosis is to reduce the urine pH to less than 5.3 through an increase in hydrogen ion excretion in the form of ammonium. A urine pH of 6.5 is highly suggestive of type 1 (distal) RTA and its associated impairment of distal acidification. Treatment with sodium bicarbonate to correct the acidosis and associated complications is warranted.

A distal RTA would account for her past medical history of renal stones. Acidemia promotes both increased calcium phosphate release from bone (with subsequent hypercalciuria) and enhanced citrate reabsorption in the proximal renal tubules, leading to decreased urinary citrate. Citrate inhibits calcium stone formation. The increased calcium load to renal tubules in addition to decreased urinary citrate both lead to increased precipitation of calcium stones in the genitourinary tract.

A diagnosis of distal RTA should prompt evaluation for specific etiologies, such as Sjögren’s syndrome or SLE. While not diagnostic of any specific condition, low C3 and C4 levels suggest immune complex formation with related complement consumption, contributing to hypocomplementemia. The diagnosis of RTA may occur among patients with Sjögren’s syndrome in the absence of overt evidence of sicca syndrome (xerostomia and keratoconjunctivitis sicca). Other etiologies of distal RTA include conditions leading to hypercalciuria, such as hyperparathyroidism and idiopathic hypercalciuria, hereditary causes, toxins such as toluene, and drugs such as amphotericin B, lithium carbonate, and ibuprofen.

Her antinuclear antibody titer was >1:1280 (normal: <80). Anti-SSA and -SSB antibodies were both positive, with a titer >100 (normal: <20). Rheumatoid factor was positive at 22 IU/mL (normal: 0-14). Anti-smith, anti-double stranded DNA, and anti-ribonucleoprotein antibodies were negative.

Sjögren’s syndrome appears to be the ultimate etiology of this patient’s distal RTA. The diagnosis of Sjögren’s is more classically made in the presence of lacrimal and/or salivary dysfunction and confirmed with compatible autoantibodies. In the absence of dry eyes or dry mouth, attention should be focused on her skin findings. Cutaneous vasculitis does occur in a small percentage of Sjögren’s syndrome cases. Urticarial lesions have been reported in this subset, and skin biopsy would further support the diagnosis.

Treatment of Sjögren’s syndrome with immunosuppressive therapy may ameliorate renal parenchymal pathology and improve her profound metabolic disturbances.

On further questioning, she described several months of mild xerostomia, which resulted in increased consumption of fluids. She did not have keratoconjunctivitis sicca. Biopsy of her urticarial rash demonstrated a leukocytoclastic vasculitis with eosinophilic infiltration (Figure 1). Renal biopsy with hematoxylin and eosin staining, immunofluorescence, and electron microscopy demonstrated an immune complex-mediated glomerulonephritis and moderate tubulointerstitial nephritis (Figure 2). A diagnosis of Sjögren’s syndrome was made based on the patient’s xerostomia, high titers of antinuclear antibodies, SSA and SSB antibodies, positive rheumatoid factor, hypocomplementemia, and systemic manifestations associated with Sjögren’s syndrome, including distal RTA, nephrolithiasis, and hives, with histologic evidence of leukocytoclastic vasculitis.

She received aggressive potassium and bicarbonate repletion and, several days later, had normalization of both. Her weakness and myalgia rapidly improved concomitantly with the correction of her hypokalemia. Five days later she was ambulating independently and discharged with potassium citrate and prednisone therapy. She had improved fatigue and rash at a 1-month follow-up with rheumatology. As an outpatient, she was started on azathioprine and slowly tapered off her steroids. Over the next several months, she had normal potassium, bicarbonate, and renal function, although she did require lithotripsy for an obstructive renal stone.

RTA should be considered in the differential diagnosis of an unexplained normal anion gap metabolic acidosis. There are 3 major types of RTAs, with different characteristics. In type 1 (distal) RTA, the primary defect is impaired distal acidification of the urine. Distal RTA commonly presents with hypokalemia, calciuria (often presenting as renal stones), and a positive UAG.¹ In type 2 (proximal) RTA, the primary defect is impaired bicarbonate reabsorption, leading to bicarbonate wasting in the urine. Proximal RTAs can be secondary to an isolated defect in bicarbonate reabsorption or generalized proximal renal tubule dysfunction (Fanconi syndrome).¹ A type 4 RTA is characterized by hypoaldosteronism, presenting usually with a mild nonanion gap metabolic acidosis and hyperkalemia. This patient’s history of renal stones, hypokalemia, and positive UAG supported a type 1 (distal) RTA. Distal RTA is often idiopathic, but initial evaluation should include a review of medications and investigation into an underlying systemic disorder (eg, plasma cell dyscrasia or autoimmune disease). This would include eliciting a possible history of xerostomia and xerophthalmia, together with testing of SSA (Ro) and SSB (La) antibodies, to assess for Sjögren’s syndrome. In addition, checking serum calcium to assess for hyperparathyroidism or familial idiopathic hypercalciuria and a review of medications, such as lithium and amphotericin,¹ may uncover other secondary causes of distal RTA.

While Sjögren’s syndrome primarily affects salivary and lacrimal glands, leading to dry mouth and dry eyes, respectively, extraglandular manifestations are common, with fatigue and arthralgia occurring in half of patients. Extra-glandular involvement also often includes the skin and kidneys but can affect several other organ systems, including the central nervous system, heart, lungs, bone marrow, and lymph nodes.²

There are many cutaneous manifestations of Sjögren’s syndrome.³ Xerosis, or xeroderma, is the most common and is characterized by dry, scaly skin. Cutaneous vasculitis can occur in 10% of patients with Sjögren’s syndrome and often presents with palpable purpura or diffuse urticarial lesions, as in our patient.⁴ Erythematous maculopapules and cryoglobulinemic vasculitis may also occur.⁴ A less common skin manifestation is annular erythema, presenting as an indurated, ring-like lesion.⁵

Chronic tubulointerstitial nephritis is the most common renal manifestation of Sjögren’s syndrome.⁶ This often pre-sents with a mild elevated serum creatinine and a distal RTA, leading to hypokalemia, as in the case discussed. Distal RTA is well described, occurring in one-quarter of patients with Sjögren’s syndrome.⁷ The pathophysiology leading to distal RTA in Sjögren’s syndrome is thought to arise from autoimmune injury to the H(+)-ATPase pump in the renal collecting tubules, leading to decreased distal proton secretion.^8,9 Younger adults with Sjögren’s syndrome, in the third and fourth decades of life, have a predilection to develop tubulointerstitial inflammation, distal RTA, and nephrolithiasis, as in the present case.⁶ Sjögren’s syndrome less commonly presents with membranoproliferative glomerulonephritis or membranous nephropathy.^10,11 Cryoglobulinemia-associated hypocomplementemia and glomerulonephritis may also occur with Sjögren’s syndrome, yet glomerular lesions are less common than is tubulointerstitial inflammation. The patient discussed had proteinuria and evidence of immune complex-mediated glomerulonephritis.

Treatment of sicca symptoms is generally supportive. It includes artificial tears, encouragement of good hydration, salivary stimulants, and maintaining good oral hygiene. Pilocarpine, a cholinergic parasympathomimetic agent, is approved by the Food and Drug Administration to treat dry mouth associated with Sjögren’s syndrome. The treatment of extraglandular manifestations depends on the organ(s) involved. More severe presentations, such as vasculitis and glomerulonephritis, often require immunosuppressive therapy with systemic glucocorticoids, cyclophosphamide, azathioprine, or other immunosuppressive agents,¹² including rituximab. RTA often necessitates treatment with oral bicarbonate and supplemental potassium repletion.

The base rate of disease (ie, prevalence of disease) influences a diagnostician’s pretest probability of a given diagnosis. The discussant briefly considered rare causes of hives (eg, vasculitis) but appropriately fine-tuned their differential for the patient’s hypokalemia and RTA. Once the diagnosis of Sjögren’s syndrome was made with certainty, the clinician was able to revisit the patient’s rash with a new lens. Urticarial vasculitis suddenly became a plausible consideration, despite its rarity (compared to allergic causes of hives) because of the direct link to the underlying autoimmune condition, which affected both the proximal muscles and distal nephrons.

• Evaluation of patients with weakness starts with determining true muscle weakness (ie, pathology involving the brain, spinal cord, peripheral nerve, neuromuscular junction, and/or muscle) from asthenia.
• Distal RTA should be considered in patients with a nonanion gap metabolic acidosis and hypokalemia.
• Sjögren’s syndrome has many extraglandular clinical manifestations, including vasculitis, urticaria, tubulointerstitial renal inflammation, glomerulonephritis, and lymphoma.

Acknowledgment

The authors thank Virgilius Cornea, MD, for his interpretation of the pathologic images.

Disclosure

Dr. Manesh is supported by the Jeremiah A. Barondess Fellowship in the Clinical Transaction of the New York Academy of Medicine, in collaboration with the Accreditation Council for Graduate Medical Education (ACGME). The authors declare no conflicts of interests.

A previously healthy 30-year-old woman presented to the emergency department with 2 weeks of weakness.

True muscle weakness must be distinguished from the more common causes of asthenia. Many systemic disorders produce fatigue, with resulting functional limitation that is often interpreted by patients as weakness. Initial history should focus on conditions producing fatigue, such as cardiopulmonary disease, anemia, connective tissue disease, depression or cachexia related to malignancy, infection, or other inflammatory states. Careful questioning may reveal evidence of dyspnea, poor exercise tolerance, or joint pain as an alternative to actual loss of muscle power. If true weakness is still suspected, attention should be focused on the pattern, onset, anatomic site, and progression of weakness. Muscle weakness is often characterized by difficulty with specific tasks, such as climbing stairs, rising from a chair, raising a hand, or using cutlery. The physical examination is critical in determining whether weakness is due to true loss of motor power. The differential diagnosis of weakness is broad and includes neurologic, infectious, endocrine, inflammatory, genetic, metabolic, and drug-induced etiologies.

She initially experienced 3 days of mild cramps and soreness in her thighs. She then developed weakness that began in her thighs and progressed to involve her lower legs and upper and lower arms. She had difficulty combing her hair. She required the use of her arms to get up from a chair. She grasped onto objects to aid in ambulation around the house. In addition, she described 1 year of moderate fatigue but no fever, weight loss, dyspnea, dysphagia, visual changes, paresthesias, bowel or bladder incontinence, back pain, or preceding gastrointestinal or respiratory illness. She had experienced diffuse intermittent hives, most prominent in her chest and upper arms, for the past several weeks.

History certainly supports true weakness but will need to be confirmed on examination. The distribution began as proximal but now appears diffuse. The presence of myalgia and cramping raises the possibility of noninflammatory myopathies, which are usually more insidious in onset. A severe electrolyte disturbance would be possible, based on the diffuse nature of weakness that was preceded by cramping. The distribution of weakness and lack of bowel or bladder incontinence is reassuring and suggests against a spinal cord disorder; however, a high index of suspicion must be maintained for myelopathy because delayed treatment might result in irreversible paralysis.

The patient’s course also includes hives. Common causes of hives include infections and allergic reactions to medications, foods, and insect stings. Urticaria may also result from systemic disorders, such as vasculitis, lupus, lymphoma, mastocytosis, and paraproteinemias, which can be associated with weakness and fatigue. Although severe weakness in combination with hives makes an infectious and allergic reaction less likely, we still seek to ascertain if the evolving chief complaints of weakness and hives are the result of a single unifying and evolving multisystem disorder or are distinct and unrelated processes.

Her past medical history included fibromyalgia, kidney stones, and gastroesophageal reflux disease. One week prior to presentation, she was prescribed prednisone 60 mg daily for the treatment of hives; the dose had been tapered to 40 mg at presentation, with mild improvement of hives. She recently started doxepin for fibromyalgia and insomnia. She lived at home with her husband and 8-year-old child. She worked as a clerk in a pest control office and denied any pesticide exposure. She denied tobacco, alcohol, or illicit drug use. Her family history included systemic lupus erythematosus (SLE) in her mother and maternal aunt.

Glucocorticoids are associated with myopathy; however, the weakness preceded steroid therapy. Thus, unless there was unknown exposure to high-dose steroid medication to treat recurrent episodes of urticaria earlier in her course, glucocorticoid-related myopathy is unlikely. Fibromyalgia might cause the perception of weakness from pain. However, the history of difficulty combing her hair and rising from a chair suggests actual loss of motor power. The side effects of her medications, such as newly started doxepin, must be reviewed. A family history of SLE raises concern for rheumatologic conditions; however, one might expect improvement with steroid therapy.

On physical examination, her temperature was 36.9 °C, blood pressure 126/93 mmHg, pulse 81 beats per minute, respiratory rate 16 breaths per minute, and oxygen saturation 100% on ambient air. Her cardiopulmonary examination was normal. Her abdomen was nontender and without hepatosplenomegaly. Her strength was 2 out of 5 in proximal and distal legs, bilaterally, and 4 out of 5 in proximal and distal upper extremities. She had normal muscle tone without fasciculations or atrophy. Her joints were without edema, erythema, or impaired range of motion. She had normal sensation to light touch in arms and legs. Her reflexes were 2+ in the patellar, Achilles, and brachioradialis tendons. She had no lymphadenopathy, mucosal ulcerations, or alopecia. A skin examination revealed smooth, slightly elevated, and faded pink wheals that were diffuse but most prominent in upper arms and chest.

Physical examination confirms the presence of true muscle weakness. The differential diagnosis is narrowed by several findings, both positive and negative, elicited in the examination. The diffuse nature of the weakness eliminates focal central nervous system lesions, such as stroke, intracranial mass lesions, or demyelinating white matter foci. Combining this finding with normal reflexes and history of preceding myalgias makes electrolyte-induced and inflammatory (eg, polymyositis) myopathies more likely. The normal deep tendon reflexes and the absence of a delayed relaxation phase lower the likelihood of hypothyroidism. 

Diseases originating from the neuromuscular junction, such as myasthenia gravis, may also present with weakness and normal reflexes, although this pattern of weakness would be atypical; myasthenia gravis classically presents with fatigable weakness and ocular findings of diplopia and/or ptosis. First-tier testing should include a complete blood count to evaluate for eosinophilia, comprehensive metabolic panel, and urinalysis for myoglobinuria, thyroid stimulating hormone, and muscle enzymes. 


Results of a complete blood count demonstrated a leukocyte count of 16.1 k/uL with 82% neutrophils, 13% lymphocytes, 5% monocytes, and 0% eosinophils. Hemoglobin was 13.2 g/dL, and platelet count 226 k/uL. Sodium was 136 mmol/L, potassium 1.5 mmol/L, chloride 115 mmol/L, bicarbonate 12 mmol/L, blood urea nitrogen 26 mg/dL, creatinine 1.0 mg/dL (baseline creatinine: 0.6), and glucose 102 mg/dL. Calcium was 9.4 mg/dL, magnesium 2.6 mg/dL, phosphorus 1.8 mg/dL, CK 501 U/L (normal: 40-230), and TSH 5.48 uIU/mL (normal: 0.5-4). Aspartate aminotransferase was 64 U/L, alanine aminotransferase 23 U/L, alkaline phosphatase 66 U/L, bilirubin 0.9 mg/dL, albumin 3.8 g/dL, and total protein 8.7 g/dL (normal: 6.2-7.8). Human immunodeficiency virus antibody screen was negative. An electrocardiogram revealed normal sinus rhythm, flattened T waves, and prominent U waves.

Potassium losses are classically categorized into 1 of 3 groups: renal losses, gastrointestinal losses, or transcellular shifts. Without a clear history of diuretic use, renal losses may not be apparent on history and examination. In contrast, gastrointestinal losses are almost always evidenced by a history of vomiting and/or diarrhea, with rare exceptions, including unreported laxative abuse or surreptitious vomiting. Transcellular potassium shifts can be seen in states of increased insulin or beta-adrenergic activity and alkalosis and result from both primary and secondary causes of hypokalemic periodic paralysis.

The presence of a reduced serum bicarbonate and elevated chloride concentration suggests a normal anion gap metabolic acidosis. Many conditions associated with normal anion gap metabolic acidosis are evident by history, such as diarrhea. In enigmatic cases such as this, it will be important to take a stepwise approach that includes an evaluation for urinary potassium losses and assessment of acid-base status. An unexplained normal anion gap metabolic acidosis combined with hypokalemia raises suspicion for a distal renal tubular acidosis (RTA). Additional testing to evaluate for a possible RTA should include the assessment of urinary electrolytes and urinary pH. The hypokalemia explains her weakness, but the etiology of such profound hypokalemia is not evident, nor is it clear how it relates to her hives.

The severity of the hypokalemia, combined with electrocardiogram changes, necessitates rapid intravenous potassium repletion, telemetry monitoring, and frequent serum potassium measurement. Treatment of her metabolic acidosis is more nuanced and depends upon both the severity of disturbance and the suspicion of whether the etiology is transcellular shift, potassium depletion, or both.

Urine studies demonstrated a urine specific gravity of 1.006 (normal: 1.001-1.030), urine pH was 6.5 (normal: 5-6.5), trace leukocyte esterase, negative nitrite, 30 mg/dL of protein (normal: <15), sodium 64 mmol/L (normal: 40-220), potassium 17 mmol/L (normal: 25-125), and chloride 71 mmol/L (normal: 110-250). Urine microscopy demonstrated 3 red blood cells per high power field (normal: 0-1), 4 white blood cells per high power field (normal: 0-4), 4+ bacteria per high power field, and no red blood cell casts. Urine protein-to-creatinine ratio was 1.6. C3 and C4 complement levels were 53 mg/dL (normal: 80-165) and 12 mg/dL (normal: 15-49), respectively. C-reactive protein was <0.5 (normal: 0-0.9), and erythrocyte sedimentation rate was 16 mm/hour (normal: 0-20).

A calculation of the urine anion gap (UAG; [urine sodium + urine potassium] – urine chloride) yields a UAG of 10 mq/L. A positive UAG, together with a nongap metabolic acidosis, should prompt the consideration of RTA. The normal renal response to acidosis is to reduce the urine pH to less than 5.3 through an increase in hydrogen ion excretion in the form of ammonium. A urine pH of 6.5 is highly suggestive of type 1 (distal) RTA and its associated impairment of distal acidification. Treatment with sodium bicarbonate to correct the acidosis and associated complications is warranted.

A distal RTA would account for her past medical history of renal stones. Acidemia promotes both increased calcium phosphate release from bone (with subsequent hypercalciuria) and enhanced citrate reabsorption in the proximal renal tubules, leading to decreased urinary citrate. Citrate inhibits calcium stone formation. The increased calcium load to renal tubules in addition to decreased urinary citrate both lead to increased precipitation of calcium stones in the genitourinary tract.

A diagnosis of distal RTA should prompt evaluation for specific etiologies, such as Sjögren’s syndrome or SLE. While not diagnostic of any specific condition, low C3 and C4 levels suggest immune complex formation with related complement consumption, contributing to hypocomplementemia. The diagnosis of RTA may occur among patients with Sjögren’s syndrome in the absence of overt evidence of sicca syndrome (xerostomia and keratoconjunctivitis sicca). Other etiologies of distal RTA include conditions leading to hypercalciuria, such as hyperparathyroidism and idiopathic hypercalciuria, hereditary causes, toxins such as toluene, and drugs such as amphotericin B, lithium carbonate, and ibuprofen.

Her antinuclear antibody titer was >1:1280 (normal: <80). Anti-SSA and -SSB antibodies were both positive, with a titer >100 (normal: <20). Rheumatoid factor was positive at 22 IU/mL (normal: 0-14). Anti-smith, anti-double stranded DNA, and anti-ribonucleoprotein antibodies were negative.

Sjögren’s syndrome appears to be the ultimate etiology of this patient’s distal RTA. The diagnosis of Sjögren’s is more classically made in the presence of lacrimal and/or salivary dysfunction and confirmed with compatible autoantibodies. In the absence of dry eyes or dry mouth, attention should be focused on her skin findings. Cutaneous vasculitis does occur in a small percentage of Sjögren’s syndrome cases. Urticarial lesions have been reported in this subset, and skin biopsy would further support the diagnosis.

Treatment of Sjögren’s syndrome with immunosuppressive therapy may ameliorate renal parenchymal pathology and improve her profound metabolic disturbances.

On further questioning, she described several months of mild xerostomia, which resulted in increased consumption of fluids. She did not have keratoconjunctivitis sicca. Biopsy of her urticarial rash demonstrated a leukocytoclastic vasculitis with eosinophilic infiltration (Figure 1). Renal biopsy with hematoxylin and eosin staining, immunofluorescence, and electron microscopy demonstrated an immune complex-mediated glomerulonephritis and moderate tubulointerstitial nephritis (Figure 2). A diagnosis of Sjögren’s syndrome was made based on the patient’s xerostomia, high titers of antinuclear antibodies, SSA and SSB antibodies, positive rheumatoid factor, hypocomplementemia, and systemic manifestations associated with Sjögren’s syndrome, including distal RTA, nephrolithiasis, and hives, with histologic evidence of leukocytoclastic vasculitis.

She received aggressive potassium and bicarbonate repletion and, several days later, had normalization of both. Her weakness and myalgia rapidly improved concomitantly with the correction of her hypokalemia. Five days later she was ambulating independently and discharged with potassium citrate and prednisone therapy. She had improved fatigue and rash at a 1-month follow-up with rheumatology. As an outpatient, she was started on azathioprine and slowly tapered off her steroids. Over the next several months, she had normal potassium, bicarbonate, and renal function, although she did require lithotripsy for an obstructive renal stone.

RTA should be considered in the differential diagnosis of an unexplained normal anion gap metabolic acidosis. There are 3 major types of RTAs, with different characteristics. In type 1 (distal) RTA, the primary defect is impaired distal acidification of the urine. Distal RTA commonly presents with hypokalemia, calciuria (often presenting as renal stones), and a positive UAG.¹ In type 2 (proximal) RTA, the primary defect is impaired bicarbonate reabsorption, leading to bicarbonate wasting in the urine. Proximal RTAs can be secondary to an isolated defect in bicarbonate reabsorption or generalized proximal renal tubule dysfunction (Fanconi syndrome).¹ A type 4 RTA is characterized by hypoaldosteronism, presenting usually with a mild nonanion gap metabolic acidosis and hyperkalemia. This patient’s history of renal stones, hypokalemia, and positive UAG supported a type 1 (distal) RTA. Distal RTA is often idiopathic, but initial evaluation should include a review of medications and investigation into an underlying systemic disorder (eg, plasma cell dyscrasia or autoimmune disease). This would include eliciting a possible history of xerostomia and xerophthalmia, together with testing of SSA (Ro) and SSB (La) antibodies, to assess for Sjögren’s syndrome. In addition, checking serum calcium to assess for hyperparathyroidism or familial idiopathic hypercalciuria and a review of medications, such as lithium and amphotericin,¹ may uncover other secondary causes of distal RTA.

While Sjögren’s syndrome primarily affects salivary and lacrimal glands, leading to dry mouth and dry eyes, respectively, extraglandular manifestations are common, with fatigue and arthralgia occurring in half of patients. Extra-glandular involvement also often includes the skin and kidneys but can affect several other organ systems, including the central nervous system, heart, lungs, bone marrow, and lymph nodes.²

There are many cutaneous manifestations of Sjögren’s syndrome.³ Xerosis, or xeroderma, is the most common and is characterized by dry, scaly skin. Cutaneous vasculitis can occur in 10% of patients with Sjögren’s syndrome and often presents with palpable purpura or diffuse urticarial lesions, as in our patient.⁴ Erythematous maculopapules and cryoglobulinemic vasculitis may also occur.⁴ A less common skin manifestation is annular erythema, presenting as an indurated, ring-like lesion.⁵

Chronic tubulointerstitial nephritis is the most common renal manifestation of Sjögren’s syndrome.⁶ This often pre-sents with a mild elevated serum creatinine and a distal RTA, leading to hypokalemia, as in the case discussed. Distal RTA is well described, occurring in one-quarter of patients with Sjögren’s syndrome.⁷ The pathophysiology leading to distal RTA in Sjögren’s syndrome is thought to arise from autoimmune injury to the H(+)-ATPase pump in the renal collecting tubules, leading to decreased distal proton secretion.^8,9 Younger adults with Sjögren’s syndrome, in the third and fourth decades of life, have a predilection to develop tubulointerstitial inflammation, distal RTA, and nephrolithiasis, as in the present case.⁶ Sjögren’s syndrome less commonly presents with membranoproliferative glomerulonephritis or membranous nephropathy.^10,11 Cryoglobulinemia-associated hypocomplementemia and glomerulonephritis may also occur with Sjögren’s syndrome, yet glomerular lesions are less common than is tubulointerstitial inflammation. The patient discussed had proteinuria and evidence of immune complex-mediated glomerulonephritis.

Treatment of sicca symptoms is generally supportive. It includes artificial tears, encouragement of good hydration, salivary stimulants, and maintaining good oral hygiene. Pilocarpine, a cholinergic parasympathomimetic agent, is approved by the Food and Drug Administration to treat dry mouth associated with Sjögren’s syndrome. The treatment of extraglandular manifestations depends on the organ(s) involved. More severe presentations, such as vasculitis and glomerulonephritis, often require immunosuppressive therapy with systemic glucocorticoids, cyclophosphamide, azathioprine, or other immunosuppressive agents,¹² including rituximab. RTA often necessitates treatment with oral bicarbonate and supplemental potassium repletion.

The base rate of disease (ie, prevalence of disease) influences a diagnostician’s pretest probability of a given diagnosis. The discussant briefly considered rare causes of hives (eg, vasculitis) but appropriately fine-tuned their differential for the patient’s hypokalemia and RTA. Once the diagnosis of Sjögren’s syndrome was made with certainty, the clinician was able to revisit the patient’s rash with a new lens. Urticarial vasculitis suddenly became a plausible consideration, despite its rarity (compared to allergic causes of hives) because of the direct link to the underlying autoimmune condition, which affected both the proximal muscles and distal nephrons.

• Evaluation of patients with weakness starts with determining true muscle weakness (ie, pathology involving the brain, spinal cord, peripheral nerve, neuromuscular junction, and/or muscle) from asthenia.
• Distal RTA should be considered in patients with a nonanion gap metabolic acidosis and hypokalemia.
• Sjögren’s syndrome has many extraglandular clinical manifestations, including vasculitis, urticaria, tubulointerstitial renal inflammation, glomerulonephritis, and lymphoma.

Acknowledgment

The authors thank Virgilius Cornea, MD, for his interpretation of the pathologic images.

Disclosure

Dr. Manesh is supported by the Jeremiah A. Barondess Fellowship in the Clinical Transaction of the New York Academy of Medicine, in collaboration with the Accreditation Council for Graduate Medical Education (ACGME). The authors declare no conflicts of interests.

A previously healthy 30-year-old woman presented to the emergency department with 2 weeks of weakness.

True muscle weakness must be distinguished from the more common causes of asthenia. Many systemic disorders produce fatigue, with resulting functional limitation that is often interpreted by patients as weakness. Initial history should focus on conditions producing fatigue, such as cardiopulmonary disease, anemia, connective tissue disease, depression or cachexia related to malignancy, infection, or other inflammatory states. Careful questioning may reveal evidence of dyspnea, poor exercise tolerance, or joint pain as an alternative to actual loss of muscle power. If true weakness is still suspected, attention should be focused on the pattern, onset, anatomic site, and progression of weakness. Muscle weakness is often characterized by difficulty with specific tasks, such as climbing stairs, rising from a chair, raising a hand, or using cutlery. The physical examination is critical in determining whether weakness is due to true loss of motor power. The differential diagnosis of weakness is broad and includes neurologic, infectious, endocrine, inflammatory, genetic, metabolic, and drug-induced etiologies.

She initially experienced 3 days of mild cramps and soreness in her thighs. She then developed weakness that began in her thighs and progressed to involve her lower legs and upper and lower arms. She had difficulty combing her hair. She required the use of her arms to get up from a chair. She grasped onto objects to aid in ambulation around the house. In addition, she described 1 year of moderate fatigue but no fever, weight loss, dyspnea, dysphagia, visual changes, paresthesias, bowel or bladder incontinence, back pain, or preceding gastrointestinal or respiratory illness. She had experienced diffuse intermittent hives, most prominent in her chest and upper arms, for the past several weeks.

History certainly supports true weakness but will need to be confirmed on examination. The distribution began as proximal but now appears diffuse. The presence of myalgia and cramping raises the possibility of noninflammatory myopathies, which are usually more insidious in onset. A severe electrolyte disturbance would be possible, based on the diffuse nature of weakness that was preceded by cramping. The distribution of weakness and lack of bowel or bladder incontinence is reassuring and suggests against a spinal cord disorder; however, a high index of suspicion must be maintained for myelopathy because delayed treatment might result in irreversible paralysis.

The patient’s course also includes hives. Common causes of hives include infections and allergic reactions to medications, foods, and insect stings. Urticaria may also result from systemic disorders, such as vasculitis, lupus, lymphoma, mastocytosis, and paraproteinemias, which can be associated with weakness and fatigue. Although severe weakness in combination with hives makes an infectious and allergic reaction less likely, we still seek to ascertain if the evolving chief complaints of weakness and hives are the result of a single unifying and evolving multisystem disorder or are distinct and unrelated processes.

Her past medical history included fibromyalgia, kidney stones, and gastroesophageal reflux disease. One week prior to presentation, she was prescribed prednisone 60 mg daily for the treatment of hives; the dose had been tapered to 40 mg at presentation, with mild improvement of hives. She recently started doxepin for fibromyalgia and insomnia. She lived at home with her husband and 8-year-old child. She worked as a clerk in a pest control office and denied any pesticide exposure. She denied tobacco, alcohol, or illicit drug use. Her family history included systemic lupus erythematosus (SLE) in her mother and maternal aunt.

Glucocorticoids are associated with myopathy; however, the weakness preceded steroid therapy. Thus, unless there was unknown exposure to high-dose steroid medication to treat recurrent episodes of urticaria earlier in her course, glucocorticoid-related myopathy is unlikely. Fibromyalgia might cause the perception of weakness from pain. However, the history of difficulty combing her hair and rising from a chair suggests actual loss of motor power. The side effects of her medications, such as newly started doxepin, must be reviewed. A family history of SLE raises concern for rheumatologic conditions; however, one might expect improvement with steroid therapy.

On physical examination, her temperature was 36.9 °C, blood pressure 126/93 mmHg, pulse 81 beats per minute, respiratory rate 16 breaths per minute, and oxygen saturation 100% on ambient air. Her cardiopulmonary examination was normal. Her abdomen was nontender and without hepatosplenomegaly. Her strength was 2 out of 5 in proximal and distal legs, bilaterally, and 4 out of 5 in proximal and distal upper extremities. She had normal muscle tone without fasciculations or atrophy. Her joints were without edema, erythema, or impaired range of motion. She had normal sensation to light touch in arms and legs. Her reflexes were 2+ in the patellar, Achilles, and brachioradialis tendons. She had no lymphadenopathy, mucosal ulcerations, or alopecia. A skin examination revealed smooth, slightly elevated, and faded pink wheals that were diffuse but most prominent in upper arms and chest.

Physical examination confirms the presence of true muscle weakness. The differential diagnosis is narrowed by several findings, both positive and negative, elicited in the examination. The diffuse nature of the weakness eliminates focal central nervous system lesions, such as stroke, intracranial mass lesions, or demyelinating white matter foci. Combining this finding with normal reflexes and history of preceding myalgias makes electrolyte-induced and inflammatory (eg, polymyositis) myopathies more likely. The normal deep tendon reflexes and the absence of a delayed relaxation phase lower the likelihood of hypothyroidism. 

Diseases originating from the neuromuscular junction, such as myasthenia gravis, may also present with weakness and normal reflexes, although this pattern of weakness would be atypical; myasthenia gravis classically presents with fatigable weakness and ocular findings of diplopia and/or ptosis. First-tier testing should include a complete blood count to evaluate for eosinophilia, comprehensive metabolic panel, and urinalysis for myoglobinuria, thyroid stimulating hormone, and muscle enzymes. 


Results of a complete blood count demonstrated a leukocyte count of 16.1 k/uL with 82% neutrophils, 13% lymphocytes, 5% monocytes, and 0% eosinophils. Hemoglobin was 13.2 g/dL, and platelet count 226 k/uL. Sodium was 136 mmol/L, potassium 1.5 mmol/L, chloride 115 mmol/L, bicarbonate 12 mmol/L, blood urea nitrogen 26 mg/dL, creatinine 1.0 mg/dL (baseline creatinine: 0.6), and glucose 102 mg/dL. Calcium was 9.4 mg/dL, magnesium 2.6 mg/dL, phosphorus 1.8 mg/dL, CK 501 U/L (normal: 40-230), and TSH 5.48 uIU/mL (normal: 0.5-4). Aspartate aminotransferase was 64 U/L, alanine aminotransferase 23 U/L, alkaline phosphatase 66 U/L, bilirubin 0.9 mg/dL, albumin 3.8 g/dL, and total protein 8.7 g/dL (normal: 6.2-7.8). Human immunodeficiency virus antibody screen was negative. An electrocardiogram revealed normal sinus rhythm, flattened T waves, and prominent U waves.

Potassium losses are classically categorized into 1 of 3 groups: renal losses, gastrointestinal losses, or transcellular shifts. Without a clear history of diuretic use, renal losses may not be apparent on history and examination. In contrast, gastrointestinal losses are almost always evidenced by a history of vomiting and/or diarrhea, with rare exceptions, including unreported laxative abuse or surreptitious vomiting. Transcellular potassium shifts can be seen in states of increased insulin or beta-adrenergic activity and alkalosis and result from both primary and secondary causes of hypokalemic periodic paralysis.

The presence of a reduced serum bicarbonate and elevated chloride concentration suggests a normal anion gap metabolic acidosis. Many conditions associated with normal anion gap metabolic acidosis are evident by history, such as diarrhea. In enigmatic cases such as this, it will be important to take a stepwise approach that includes an evaluation for urinary potassium losses and assessment of acid-base status. An unexplained normal anion gap metabolic acidosis combined with hypokalemia raises suspicion for a distal renal tubular acidosis (RTA). Additional testing to evaluate for a possible RTA should include the assessment of urinary electrolytes and urinary pH. The hypokalemia explains her weakness, but the etiology of such profound hypokalemia is not evident, nor is it clear how it relates to her hives.

The severity of the hypokalemia, combined with electrocardiogram changes, necessitates rapid intravenous potassium repletion, telemetry monitoring, and frequent serum potassium measurement. Treatment of her metabolic acidosis is more nuanced and depends upon both the severity of disturbance and the suspicion of whether the etiology is transcellular shift, potassium depletion, or both.

Urine studies demonstrated a urine specific gravity of 1.006 (normal: 1.001-1.030), urine pH was 6.5 (normal: 5-6.5), trace leukocyte esterase, negative nitrite, 30 mg/dL of protein (normal: <15), sodium 64 mmol/L (normal: 40-220), potassium 17 mmol/L (normal: 25-125), and chloride 71 mmol/L (normal: 110-250). Urine microscopy demonstrated 3 red blood cells per high power field (normal: 0-1), 4 white blood cells per high power field (normal: 0-4), 4+ bacteria per high power field, and no red blood cell casts. Urine protein-to-creatinine ratio was 1.6. C3 and C4 complement levels were 53 mg/dL (normal: 80-165) and 12 mg/dL (normal: 15-49), respectively. C-reactive protein was <0.5 (normal: 0-0.9), and erythrocyte sedimentation rate was 16 mm/hour (normal: 0-20).

A calculation of the urine anion gap (UAG; [urine sodium + urine potassium] – urine chloride) yields a UAG of 10 mq/L. A positive UAG, together with a nongap metabolic acidosis, should prompt the consideration of RTA. The normal renal response to acidosis is to reduce the urine pH to less than 5.3 through an increase in hydrogen ion excretion in the form of ammonium. A urine pH of 6.5 is highly suggestive of type 1 (distal) RTA and its associated impairment of distal acidification. Treatment with sodium bicarbonate to correct the acidosis and associated complications is warranted.

A distal RTA would account for her past medical history of renal stones. Acidemia promotes both increased calcium phosphate release from bone (with subsequent hypercalciuria) and enhanced citrate reabsorption in the proximal renal tubules, leading to decreased urinary citrate. Citrate inhibits calcium stone formation. The increased calcium load to renal tubules in addition to decreased urinary citrate both lead to increased precipitation of calcium stones in the genitourinary tract.

A diagnosis of distal RTA should prompt evaluation for specific etiologies, such as Sjögren’s syndrome or SLE. While not diagnostic of any specific condition, low C3 and C4 levels suggest immune complex formation with related complement consumption, contributing to hypocomplementemia. The diagnosis of RTA may occur among patients with Sjögren’s syndrome in the absence of overt evidence of sicca syndrome (xerostomia and keratoconjunctivitis sicca). Other etiologies of distal RTA include conditions leading to hypercalciuria, such as hyperparathyroidism and idiopathic hypercalciuria, hereditary causes, toxins such as toluene, and drugs such as amphotericin B, lithium carbonate, and ibuprofen.

Her antinuclear antibody titer was >1:1280 (normal: <80). Anti-SSA and -SSB antibodies were both positive, with a titer >100 (normal: <20). Rheumatoid factor was positive at 22 IU/mL (normal: 0-14). Anti-smith, anti-double stranded DNA, and anti-ribonucleoprotein antibodies were negative.

Sjögren’s syndrome appears to be the ultimate etiology of this patient’s distal RTA. The diagnosis of Sjögren’s is more classically made in the presence of lacrimal and/or salivary dysfunction and confirmed with compatible autoantibodies. In the absence of dry eyes or dry mouth, attention should be focused on her skin findings. Cutaneous vasculitis does occur in a small percentage of Sjögren’s syndrome cases. Urticarial lesions have been reported in this subset, and skin biopsy would further support the diagnosis.

Treatment of Sjögren’s syndrome with immunosuppressive therapy may ameliorate renal parenchymal pathology and improve her profound metabolic disturbances.

On further questioning, she described several months of mild xerostomia, which resulted in increased consumption of fluids. She did not have keratoconjunctivitis sicca. Biopsy of her urticarial rash demonstrated a leukocytoclastic vasculitis with eosinophilic infiltration (Figure 1). Renal biopsy with hematoxylin and eosin staining, immunofluorescence, and electron microscopy demonstrated an immune complex-mediated glomerulonephritis and moderate tubulointerstitial nephritis (Figure 2). A diagnosis of Sjögren’s syndrome was made based on the patient’s xerostomia, high titers of antinuclear antibodies, SSA and SSB antibodies, positive rheumatoid factor, hypocomplementemia, and systemic manifestations associated with Sjögren’s syndrome, including distal RTA, nephrolithiasis, and hives, with histologic evidence of leukocytoclastic vasculitis.

She received aggressive potassium and bicarbonate repletion and, several days later, had normalization of both. Her weakness and myalgia rapidly improved concomitantly with the correction of her hypokalemia. Five days later she was ambulating independently and discharged with potassium citrate and prednisone therapy. She had improved fatigue and rash at a 1-month follow-up with rheumatology. As an outpatient, she was started on azathioprine and slowly tapered off her steroids. Over the next several months, she had normal potassium, bicarbonate, and renal function, although she did require lithotripsy for an obstructive renal stone.

RTA should be considered in the differential diagnosis of an unexplained normal anion gap metabolic acidosis. There are 3 major types of RTAs, with different characteristics. In type 1 (distal) RTA, the primary defect is impaired distal acidification of the urine. Distal RTA commonly presents with hypokalemia, calciuria (often presenting as renal stones), and a positive UAG.¹ In type 2 (proximal) RTA, the primary defect is impaired bicarbonate reabsorption, leading to bicarbonate wasting in the urine. Proximal RTAs can be secondary to an isolated defect in bicarbonate reabsorption or generalized proximal renal tubule dysfunction (Fanconi syndrome).¹ A type 4 RTA is characterized by hypoaldosteronism, presenting usually with a mild nonanion gap metabolic acidosis and hyperkalemia. This patient’s history of renal stones, hypokalemia, and positive UAG supported a type 1 (distal) RTA. Distal RTA is often idiopathic, but initial evaluation should include a review of medications and investigation into an underlying systemic disorder (eg, plasma cell dyscrasia or autoimmune disease). This would include eliciting a possible history of xerostomia and xerophthalmia, together with testing of SSA (Ro) and SSB (La) antibodies, to assess for Sjögren’s syndrome. In addition, checking serum calcium to assess for hyperparathyroidism or familial idiopathic hypercalciuria and a review of medications, such as lithium and amphotericin,¹ may uncover other secondary causes of distal RTA.

While Sjögren’s syndrome primarily affects salivary and lacrimal glands, leading to dry mouth and dry eyes, respectively, extraglandular manifestations are common, with fatigue and arthralgia occurring in half of patients. Extra-glandular involvement also often includes the skin and kidneys but can affect several other organ systems, including the central nervous system, heart, lungs, bone marrow, and lymph nodes.²

There are many cutaneous manifestations of Sjögren’s syndrome.³ Xerosis, or xeroderma, is the most common and is characterized by dry, scaly skin. Cutaneous vasculitis can occur in 10% of patients with Sjögren’s syndrome and often presents with palpable purpura or diffuse urticarial lesions, as in our patient.⁴ Erythematous maculopapules and cryoglobulinemic vasculitis may also occur.⁴ A less common skin manifestation is annular erythema, presenting as an indurated, ring-like lesion.⁵

Chronic tubulointerstitial nephritis is the most common renal manifestation of Sjögren’s syndrome.⁶ This often pre-sents with a mild elevated serum creatinine and a distal RTA, leading to hypokalemia, as in the case discussed. Distal RTA is well described, occurring in one-quarter of patients with Sjögren’s syndrome.⁷ The pathophysiology leading to distal RTA in Sjögren’s syndrome is thought to arise from autoimmune injury to the H(+)-ATPase pump in the renal collecting tubules, leading to decreased distal proton secretion.^8,9 Younger adults with Sjögren’s syndrome, in the third and fourth decades of life, have a predilection to develop tubulointerstitial inflammation, distal RTA, and nephrolithiasis, as in the present case.⁶ Sjögren’s syndrome less commonly presents with membranoproliferative glomerulonephritis or membranous nephropathy.^10,11 Cryoglobulinemia-associated hypocomplementemia and glomerulonephritis may also occur with Sjögren’s syndrome, yet glomerular lesions are less common than is tubulointerstitial inflammation. The patient discussed had proteinuria and evidence of immune complex-mediated glomerulonephritis.

Treatment of sicca symptoms is generally supportive. It includes artificial tears, encouragement of good hydration, salivary stimulants, and maintaining good oral hygiene. Pilocarpine, a cholinergic parasympathomimetic agent, is approved by the Food and Drug Administration to treat dry mouth associated with Sjögren’s syndrome. The treatment of extraglandular manifestations depends on the organ(s) involved. More severe presentations, such as vasculitis and glomerulonephritis, often require immunosuppressive therapy with systemic glucocorticoids, cyclophosphamide, azathioprine, or other immunosuppressive agents,¹² including rituximab. RTA often necessitates treatment with oral bicarbonate and supplemental potassium repletion.

The base rate of disease (ie, prevalence of disease) influences a diagnostician’s pretest probability of a given diagnosis. The discussant briefly considered rare causes of hives (eg, vasculitis) but appropriately fine-tuned their differential for the patient’s hypokalemia and RTA. Once the diagnosis of Sjögren’s syndrome was made with certainty, the clinician was able to revisit the patient’s rash with a new lens. Urticarial vasculitis suddenly became a plausible consideration, despite its rarity (compared to allergic causes of hives) because of the direct link to the underlying autoimmune condition, which affected both the proximal muscles and distal nephrons.

• Evaluation of patients with weakness starts with determining true muscle weakness (ie, pathology involving the brain, spinal cord, peripheral nerve, neuromuscular junction, and/or muscle) from asthenia.
• Distal RTA should be considered in patients with a nonanion gap metabolic acidosis and hypokalemia.
• Sjögren’s syndrome has many extraglandular clinical manifestations, including vasculitis, urticaria, tubulointerstitial renal inflammation, glomerulonephritis, and lymphoma.

Acknowledgment

The authors thank Virgilius Cornea, MD, for his interpretation of the pathologic images.

Disclosure

Dr. Manesh is supported by the Jeremiah A. Barondess Fellowship in the Clinical Transaction of the New York Academy of Medicine, in collaboration with the Accreditation Council for Graduate Medical Education (ACGME). The authors declare no conflicts of interests.

Given the recent rise in marijuana legalization efforts and an overall increase in the prevalence of marijuana use, it is becoming increasingly important to recognize conditions that are associated with its use. Data obtained from the National Survey on Drug Use and Health show the prevalence of marijuana use within the past month among those surveyed was 8.4% in 2014. This represents a 35% increase from the same study in 2002. Based on this survey, 2.5 million people (or ~7,000 per day) used marijuana for the first time.¹

Following the liberalization of marijuana in Colorado, the prevalence of presentation to the emergency department (ED) for cyclic vomiting nearly doubled.² During the 2016 election season, several states included legislation that increased access to marijuana on the ballot, most of which passed. There are now 28 states plus the District of Columbia that permit medical marijuana usage, and 8 of those states and the District of Columbia have laws allowing for recreational use of marijuana.³

First described in a case series by Allen and colleagues in 2004, cannabinoid hyperemesis syndrome (CHS) is indicated by recurrent episodes of nausea and vomiting with vague abdominal pain and compulsive hot bathing in the setting of chronic, often daily, cannabis use.⁴ A case of a middle-aged veteran with chronic marijuana use and recurrent, self-limited nausea and vomiting is presented here.

Case Presentation

A 45-year-old man presented to the ED with a 5-day history of persistent nausea and vomiting that began abruptly. The symptoms had been constant since onset, resulting in very little oral intake. The patient reported no hematemesis or coffee ground emesis. He noted a drop in his urine output over the previous 2 days. He also reported abdominal pain associated with the nausea. The patient characterized his pain as “dull and achy” diffuse pain that was partially relieved with emesis. His bowel movements had been regular, and he reported no diarrhea, fever, chills, or other constitutional symptoms. Additional 10-point review of systems was otherwise negative. The patient reported smoking marijuana multiple times daily for many years. The patient reported he had not used alcohol for several months.

A physical exam showed a pale and diaphoretic patient. Vital signs were significant for mild hypertension (150/75), but the patient was afebrile with a normal heart rate. An abdominal exam revealed a nontender, nondistended abdomen with no signs of rebound or guarding. The remainder of the examination was unremarkable. An initial workup showed a mild elevation of serum creatinine to 1.36 mg/dL (baseline is 1.10 mg/dL). Other workups, including complete blood count (CBC) with differential, complete metabolic panel, lipase, amylase, and urine analysis, were all unremarkable.

The patient’s urine drug screen (UDS) was positive for tetrahydrocannabinol (THC). A computed tomography (CT) scan of his abdomen and pelvis with contrast was unremarkable. The patient was admitted for his inability to tolerate oral intake and dehydration and treated supportively with IV fluids and antiemetics.

Overnight, the nursing staff reported that the patient took multiple, prolonged hot showers. Upon further questioning, he reported the hot showers significantly helped the nausea and abdominal pain. He had learned this behavior after experiencing previous episodes of self-limited nausea, vomiting, and abdominal pain.

Extensive review of his medical record revealed that the patient had, in fact, presented to the ED with similar symptoms 11 times in the prior 8 years. He was admitted on 8 occasions over that time frame. The typical hospital course included supportive care with antiemetics and IV fluids. The patient’s symptoms typically resolved within 24 to 72 hours of hospitalization. Previous evaluations included additional unremarkable CT imaging of the abdomen and pelvis. The patient also had received 2 esophagogastroduodenoscopies (EGDs), one 2 years prior and the other 5 years prior. Both EGDs showed only mild gastritis. On every check during the previous 8 years, the patient’s UDS was positive for THC.

Most of his previous admissions were attributed to viral gastroenteritis due to the self-limited nature of the symptoms. Other admissions were attributed to alcohol-induced gastritis. However, after abstaining from alcohol for long periods, the patient had continued recurrence of the symptoms and increased frequency of presentations to the ED.

The characteristics, signs, and symptoms of CHS were discussed with the patient. The patient strongly felt as though these symptoms aligned with his clinical course over the prior 8 years. At time of writing, the patient had gone 20 months without requiring hospitalization; however, he had a recent relapse of marijuana use and subsequently required hospitalization.

Discussion

As in this case, CHS often presents with refractory, self-limited nausea and vomiting with vague abdominal pain that is temporarily relieved by hot baths or showers. In the largest case series, it was noted the average age was 32 years, and the majority of subjects used marijuana at least weekly for > 2 years.⁵ Many studies categorize CHS into 3 phases: prodromal, hyperemetic, and recovery.

The prodromal, or preemetic phase, is characterized by early morning nausea without emesis and abdominal discomfort. The hyperemetic phase begins when the patient accesses the health care system via either the ED or primary care physician. This phase is characterized by intractable nausea and vomiting and may be associated with mild diffuse abdominal pain. The nausea and vomiting typically do not respond to antiemetic medications. Patients in this stage also develop a compulsive behavior of hot showers that temporarily relieve the symptoms. These behaviors are thought to be learned through their cyclical periods of emesis and may not be present during the first few hyperemetic phases. During the recovery phase, the patient returns to a baseline state of health and often ceases utilizing the hot shower. The recovery phase can last weeks to months despite continued cannabis use prior to returning to the hyperemetic phase (Figure).^6,7

Simonetto and colleagues proposed clinical criteria for the diagnosis of CHS based on their case series as well as on previously proposed criteria presented by Sontineni and colleagues.^5,8 Long-term cannabis use is required for the diagnosis. In the Simonetto and colleagues case series, the majority of patients developed symptoms within the first 5 years of cannabis use; however, Soriano and colleagues conducted a smaller case series that showed that the majority of subjects used marijuana for roughly 16 years prior to the onset of vomiting.^5,7

The major CHS features that suggest the diagnosis are severe cyclic nausea and vomiting, relief of symptoms with abstinence from cannabis, temporary symptom relief with hot bathing, abdominal pain, and at least weekly use of marijuana. Other supportive features include aged < 50 years, weight loss > 5 kg, symptoms that are worse in the morning, normal bowel habits, and negative evaluation, including laboratory, radiography, and endoscopy (Table).⁵

Treatment often is supportive with emphasis placed on marijuana cessation. Intravenous fluids often are used due to dehydration from the emesis. The use of antiemetics, such as 5-HT3 (eg, ondansetron), D2 (eg, prochlorperazine), H1 (eg, promethazine), or neurokinin-1 receptor antagonists (eg, aprepitant) can be tried, but these therapies often are ineffective. Diet can be advanced as the patient tolerates. Given that many patients are found to have a mild gastritis, H2 blockers or proton pump inhibitors may be used. Extensive counseling on marijuana cessation is needed as it is the only therapy shown to have prolonged relief of the hyperemetic phase.⁶ The length of cessation from marijuana for resolution of the cyclical hyperemesis varies from 1 to 3 months. Returning to marijuana use often results in the returning of CHS.⁵

The pathophysiology of CHS is largely unknown; however, there are several hypothesized mechanisms. Many theorize that due to the lipophilicity and long half-life of THC, a primary compound in marijuana, it accumulates in the body over time.^4,6 It is thought that this accumulation may cause toxicity in both the gastrointestinal tract as well as in the brain. Central effects on the hypothalamic-pituitary axis may play a major role, and the reason for the symptom relief of hot baths is due to a change in thermoregulation in the hypothalamus.⁵ One interesting mechanism relates to CB1 receptor activation and vasodilation within the gastrointestinal tract due to chronic THC accumulation. The relief of the abdominal pain, nausea, and vomiting with hot showers can be secondary to the vasodilation of the skin, causing a redistribution from the gut. This theorized mechanism has been referred to as “cutaneous steal.”⁹

Conclusion

With the increased prevalence of marijuana use in the U.S. over the past decade and reform in legislation taking place over the next couple of years, it is increasingly important to be able to recognize CHS to avoid frequent hospital utilization and repeated costly evaluations. Cannabinoid hyperemesis syndrome is recognized by the triad of chronic cannabis use, cyclical hyperemesis, and compulsive hot bathing.⁴

The syndrome has 3 phases. In the prodromal phase the patient has morning predominance of nausea, usually without emesis. This is followed by the hyperemesis phase, which is characterized by hyperemesis, vague abdominal pain, and learned compulsive hot bathing.

The third phase is the recovery phase, which is a return to normal behavior. During the recovery phase, if patients cease marijuana use, they remain asymptomatic; however, if patients continue to use marijuana, they often have recurrence of the hyperemesis phase.⁵ The diagnosis of cannabinoid hyperemesis syndrome is difficult as it is a diagnosis of exclusion. Patients may present to the ED many times prior to diagnosis. With the changing climate of marijuana laws, it is an important condition to consider when establishing a differential. More studies will be required to evaluate the overall prevalence of this condition as well as if there are any changes following the liberalization of marijuana laws in many states.

Given the recent rise in marijuana legalization efforts and an overall increase in the prevalence of marijuana use, it is becoming increasingly important to recognize conditions that are associated with its use. Data obtained from the National Survey on Drug Use and Health show the prevalence of marijuana use within the past month among those surveyed was 8.4% in 2014. This represents a 35% increase from the same study in 2002. Based on this survey, 2.5 million people (or ~7,000 per day) used marijuana for the first time.¹

Following the liberalization of marijuana in Colorado, the prevalence of presentation to the emergency department (ED) for cyclic vomiting nearly doubled.² During the 2016 election season, several states included legislation that increased access to marijuana on the ballot, most of which passed. There are now 28 states plus the District of Columbia that permit medical marijuana usage, and 8 of those states and the District of Columbia have laws allowing for recreational use of marijuana.³

First described in a case series by Allen and colleagues in 2004, cannabinoid hyperemesis syndrome (CHS) is indicated by recurrent episodes of nausea and vomiting with vague abdominal pain and compulsive hot bathing in the setting of chronic, often daily, cannabis use.⁴ A case of a middle-aged veteran with chronic marijuana use and recurrent, self-limited nausea and vomiting is presented here.

Case Presentation

A 45-year-old man presented to the ED with a 5-day history of persistent nausea and vomiting that began abruptly. The symptoms had been constant since onset, resulting in very little oral intake. The patient reported no hematemesis or coffee ground emesis. He noted a drop in his urine output over the previous 2 days. He also reported abdominal pain associated with the nausea. The patient characterized his pain as “dull and achy” diffuse pain that was partially relieved with emesis. His bowel movements had been regular, and he reported no diarrhea, fever, chills, or other constitutional symptoms. Additional 10-point review of systems was otherwise negative. The patient reported smoking marijuana multiple times daily for many years. The patient reported he had not used alcohol for several months.

A physical exam showed a pale and diaphoretic patient. Vital signs were significant for mild hypertension (150/75), but the patient was afebrile with a normal heart rate. An abdominal exam revealed a nontender, nondistended abdomen with no signs of rebound or guarding. The remainder of the examination was unremarkable. An initial workup showed a mild elevation of serum creatinine to 1.36 mg/dL (baseline is 1.10 mg/dL). Other workups, including complete blood count (CBC) with differential, complete metabolic panel, lipase, amylase, and urine analysis, were all unremarkable.

The patient’s urine drug screen (UDS) was positive for tetrahydrocannabinol (THC). A computed tomography (CT) scan of his abdomen and pelvis with contrast was unremarkable. The patient was admitted for his inability to tolerate oral intake and dehydration and treated supportively with IV fluids and antiemetics.

Overnight, the nursing staff reported that the patient took multiple, prolonged hot showers. Upon further questioning, he reported the hot showers significantly helped the nausea and abdominal pain. He had learned this behavior after experiencing previous episodes of self-limited nausea, vomiting, and abdominal pain.

Extensive review of his medical record revealed that the patient had, in fact, presented to the ED with similar symptoms 11 times in the prior 8 years. He was admitted on 8 occasions over that time frame. The typical hospital course included supportive care with antiemetics and IV fluids. The patient’s symptoms typically resolved within 24 to 72 hours of hospitalization. Previous evaluations included additional unremarkable CT imaging of the abdomen and pelvis. The patient also had received 2 esophagogastroduodenoscopies (EGDs), one 2 years prior and the other 5 years prior. Both EGDs showed only mild gastritis. On every check during the previous 8 years, the patient’s UDS was positive for THC.

Most of his previous admissions were attributed to viral gastroenteritis due to the self-limited nature of the symptoms. Other admissions were attributed to alcohol-induced gastritis. However, after abstaining from alcohol for long periods, the patient had continued recurrence of the symptoms and increased frequency of presentations to the ED.

The characteristics, signs, and symptoms of CHS were discussed with the patient. The patient strongly felt as though these symptoms aligned with his clinical course over the prior 8 years. At time of writing, the patient had gone 20 months without requiring hospitalization; however, he had a recent relapse of marijuana use and subsequently required hospitalization.

Discussion

As in this case, CHS often presents with refractory, self-limited nausea and vomiting with vague abdominal pain that is temporarily relieved by hot baths or showers. In the largest case series, it was noted the average age was 32 years, and the majority of subjects used marijuana at least weekly for > 2 years.⁵ Many studies categorize CHS into 3 phases: prodromal, hyperemetic, and recovery.

The prodromal, or preemetic phase, is characterized by early morning nausea without emesis and abdominal discomfort. The hyperemetic phase begins when the patient accesses the health care system via either the ED or primary care physician. This phase is characterized by intractable nausea and vomiting and may be associated with mild diffuse abdominal pain. The nausea and vomiting typically do not respond to antiemetic medications. Patients in this stage also develop a compulsive behavior of hot showers that temporarily relieve the symptoms. These behaviors are thought to be learned through their cyclical periods of emesis and may not be present during the first few hyperemetic phases. During the recovery phase, the patient returns to a baseline state of health and often ceases utilizing the hot shower. The recovery phase can last weeks to months despite continued cannabis use prior to returning to the hyperemetic phase (Figure).^6,7

Simonetto and colleagues proposed clinical criteria for the diagnosis of CHS based on their case series as well as on previously proposed criteria presented by Sontineni and colleagues.^5,8 Long-term cannabis use is required for the diagnosis. In the Simonetto and colleagues case series, the majority of patients developed symptoms within the first 5 years of cannabis use; however, Soriano and colleagues conducted a smaller case series that showed that the majority of subjects used marijuana for roughly 16 years prior to the onset of vomiting.^5,7

The major CHS features that suggest the diagnosis are severe cyclic nausea and vomiting, relief of symptoms with abstinence from cannabis, temporary symptom relief with hot bathing, abdominal pain, and at least weekly use of marijuana. Other supportive features include aged < 50 years, weight loss > 5 kg, symptoms that are worse in the morning, normal bowel habits, and negative evaluation, including laboratory, radiography, and endoscopy (Table).⁵

Treatment often is supportive with emphasis placed on marijuana cessation. Intravenous fluids often are used due to dehydration from the emesis. The use of antiemetics, such as 5-HT3 (eg, ondansetron), D2 (eg, prochlorperazine), H1 (eg, promethazine), or neurokinin-1 receptor antagonists (eg, aprepitant) can be tried, but these therapies often are ineffective. Diet can be advanced as the patient tolerates. Given that many patients are found to have a mild gastritis, H2 blockers or proton pump inhibitors may be used. Extensive counseling on marijuana cessation is needed as it is the only therapy shown to have prolonged relief of the hyperemetic phase.⁶ The length of cessation from marijuana for resolution of the cyclical hyperemesis varies from 1 to 3 months. Returning to marijuana use often results in the returning of CHS.⁵

The pathophysiology of CHS is largely unknown; however, there are several hypothesized mechanisms. Many theorize that due to the lipophilicity and long half-life of THC, a primary compound in marijuana, it accumulates in the body over time.^4,6 It is thought that this accumulation may cause toxicity in both the gastrointestinal tract as well as in the brain. Central effects on the hypothalamic-pituitary axis may play a major role, and the reason for the symptom relief of hot baths is due to a change in thermoregulation in the hypothalamus.⁵ One interesting mechanism relates to CB1 receptor activation and vasodilation within the gastrointestinal tract due to chronic THC accumulation. The relief of the abdominal pain, nausea, and vomiting with hot showers can be secondary to the vasodilation of the skin, causing a redistribution from the gut. This theorized mechanism has been referred to as “cutaneous steal.”⁹

Conclusion

With the increased prevalence of marijuana use in the U.S. over the past decade and reform in legislation taking place over the next couple of years, it is increasingly important to be able to recognize CHS to avoid frequent hospital utilization and repeated costly evaluations. Cannabinoid hyperemesis syndrome is recognized by the triad of chronic cannabis use, cyclical hyperemesis, and compulsive hot bathing.⁴

The syndrome has 3 phases. In the prodromal phase the patient has morning predominance of nausea, usually without emesis. This is followed by the hyperemesis phase, which is characterized by hyperemesis, vague abdominal pain, and learned compulsive hot bathing.

The third phase is the recovery phase, which is a return to normal behavior. During the recovery phase, if patients cease marijuana use, they remain asymptomatic; however, if patients continue to use marijuana, they often have recurrence of the hyperemesis phase.⁵ The diagnosis of cannabinoid hyperemesis syndrome is difficult as it is a diagnosis of exclusion. Patients may present to the ED many times prior to diagnosis. With the changing climate of marijuana laws, it is an important condition to consider when establishing a differential. More studies will be required to evaluate the overall prevalence of this condition as well as if there are any changes following the liberalization of marijuana laws in many states.

Given the recent rise in marijuana legalization efforts and an overall increase in the prevalence of marijuana use, it is becoming increasingly important to recognize conditions that are associated with its use. Data obtained from the National Survey on Drug Use and Health show the prevalence of marijuana use within the past month among those surveyed was 8.4% in 2014. This represents a 35% increase from the same study in 2002. Based on this survey, 2.5 million people (or ~7,000 per day) used marijuana for the first time.¹

Following the liberalization of marijuana in Colorado, the prevalence of presentation to the emergency department (ED) for cyclic vomiting nearly doubled.² During the 2016 election season, several states included legislation that increased access to marijuana on the ballot, most of which passed. There are now 28 states plus the District of Columbia that permit medical marijuana usage, and 8 of those states and the District of Columbia have laws allowing for recreational use of marijuana.³

First described in a case series by Allen and colleagues in 2004, cannabinoid hyperemesis syndrome (CHS) is indicated by recurrent episodes of nausea and vomiting with vague abdominal pain and compulsive hot bathing in the setting of chronic, often daily, cannabis use.⁴ A case of a middle-aged veteran with chronic marijuana use and recurrent, self-limited nausea and vomiting is presented here.

Case Presentation

A 45-year-old man presented to the ED with a 5-day history of persistent nausea and vomiting that began abruptly. The symptoms had been constant since onset, resulting in very little oral intake. The patient reported no hematemesis or coffee ground emesis. He noted a drop in his urine output over the previous 2 days. He also reported abdominal pain associated with the nausea. The patient characterized his pain as “dull and achy” diffuse pain that was partially relieved with emesis. His bowel movements had been regular, and he reported no diarrhea, fever, chills, or other constitutional symptoms. Additional 10-point review of systems was otherwise negative. The patient reported smoking marijuana multiple times daily for many years. The patient reported he had not used alcohol for several months.

A physical exam showed a pale and diaphoretic patient. Vital signs were significant for mild hypertension (150/75), but the patient was afebrile with a normal heart rate. An abdominal exam revealed a nontender, nondistended abdomen with no signs of rebound or guarding. The remainder of the examination was unremarkable. An initial workup showed a mild elevation of serum creatinine to 1.36 mg/dL (baseline is 1.10 mg/dL). Other workups, including complete blood count (CBC) with differential, complete metabolic panel, lipase, amylase, and urine analysis, were all unremarkable.

The patient’s urine drug screen (UDS) was positive for tetrahydrocannabinol (THC). A computed tomography (CT) scan of his abdomen and pelvis with contrast was unremarkable. The patient was admitted for his inability to tolerate oral intake and dehydration and treated supportively with IV fluids and antiemetics.

Overnight, the nursing staff reported that the patient took multiple, prolonged hot showers. Upon further questioning, he reported the hot showers significantly helped the nausea and abdominal pain. He had learned this behavior after experiencing previous episodes of self-limited nausea, vomiting, and abdominal pain.

Extensive review of his medical record revealed that the patient had, in fact, presented to the ED with similar symptoms 11 times in the prior 8 years. He was admitted on 8 occasions over that time frame. The typical hospital course included supportive care with antiemetics and IV fluids. The patient’s symptoms typically resolved within 24 to 72 hours of hospitalization. Previous evaluations included additional unremarkable CT imaging of the abdomen and pelvis. The patient also had received 2 esophagogastroduodenoscopies (EGDs), one 2 years prior and the other 5 years prior. Both EGDs showed only mild gastritis. On every check during the previous 8 years, the patient’s UDS was positive for THC.

Most of his previous admissions were attributed to viral gastroenteritis due to the self-limited nature of the symptoms. Other admissions were attributed to alcohol-induced gastritis. However, after abstaining from alcohol for long periods, the patient had continued recurrence of the symptoms and increased frequency of presentations to the ED.

The characteristics, signs, and symptoms of CHS were discussed with the patient. The patient strongly felt as though these symptoms aligned with his clinical course over the prior 8 years. At time of writing, the patient had gone 20 months without requiring hospitalization; however, he had a recent relapse of marijuana use and subsequently required hospitalization.

Discussion

As in this case, CHS often presents with refractory, self-limited nausea and vomiting with vague abdominal pain that is temporarily relieved by hot baths or showers. In the largest case series, it was noted the average age was 32 years, and the majority of subjects used marijuana at least weekly for > 2 years.⁵ Many studies categorize CHS into 3 phases: prodromal, hyperemetic, and recovery.

The prodromal, or preemetic phase, is characterized by early morning nausea without emesis and abdominal discomfort. The hyperemetic phase begins when the patient accesses the health care system via either the ED or primary care physician. This phase is characterized by intractable nausea and vomiting and may be associated with mild diffuse abdominal pain. The nausea and vomiting typically do not respond to antiemetic medications. Patients in this stage also develop a compulsive behavior of hot showers that temporarily relieve the symptoms. These behaviors are thought to be learned through their cyclical periods of emesis and may not be present during the first few hyperemetic phases. During the recovery phase, the patient returns to a baseline state of health and often ceases utilizing the hot shower. The recovery phase can last weeks to months despite continued cannabis use prior to returning to the hyperemetic phase (Figure).^6,7

Simonetto and colleagues proposed clinical criteria for the diagnosis of CHS based on their case series as well as on previously proposed criteria presented by Sontineni and colleagues.^5,8 Long-term cannabis use is required for the diagnosis. In the Simonetto and colleagues case series, the majority of patients developed symptoms within the first 5 years of cannabis use; however, Soriano and colleagues conducted a smaller case series that showed that the majority of subjects used marijuana for roughly 16 years prior to the onset of vomiting.^5,7

The major CHS features that suggest the diagnosis are severe cyclic nausea and vomiting, relief of symptoms with abstinence from cannabis, temporary symptom relief with hot bathing, abdominal pain, and at least weekly use of marijuana. Other supportive features include aged < 50 years, weight loss > 5 kg, symptoms that are worse in the morning, normal bowel habits, and negative evaluation, including laboratory, radiography, and endoscopy (Table).⁵

Treatment often is supportive with emphasis placed on marijuana cessation. Intravenous fluids often are used due to dehydration from the emesis. The use of antiemetics, such as 5-HT3 (eg, ondansetron), D2 (eg, prochlorperazine), H1 (eg, promethazine), or neurokinin-1 receptor antagonists (eg, aprepitant) can be tried, but these therapies often are ineffective. Diet can be advanced as the patient tolerates. Given that many patients are found to have a mild gastritis, H2 blockers or proton pump inhibitors may be used. Extensive counseling on marijuana cessation is needed as it is the only therapy shown to have prolonged relief of the hyperemetic phase.⁶ The length of cessation from marijuana for resolution of the cyclical hyperemesis varies from 1 to 3 months. Returning to marijuana use often results in the returning of CHS.⁵

The pathophysiology of CHS is largely unknown; however, there are several hypothesized mechanisms. Many theorize that due to the lipophilicity and long half-life of THC, a primary compound in marijuana, it accumulates in the body over time.^4,6 It is thought that this accumulation may cause toxicity in both the gastrointestinal tract as well as in the brain. Central effects on the hypothalamic-pituitary axis may play a major role, and the reason for the symptom relief of hot baths is due to a change in thermoregulation in the hypothalamus.⁵ One interesting mechanism relates to CB1 receptor activation and vasodilation within the gastrointestinal tract due to chronic THC accumulation. The relief of the abdominal pain, nausea, and vomiting with hot showers can be secondary to the vasodilation of the skin, causing a redistribution from the gut. This theorized mechanism has been referred to as “cutaneous steal.”⁹

Conclusion

With the increased prevalence of marijuana use in the U.S. over the past decade and reform in legislation taking place over the next couple of years, it is increasingly important to be able to recognize CHS to avoid frequent hospital utilization and repeated costly evaluations. Cannabinoid hyperemesis syndrome is recognized by the triad of chronic cannabis use, cyclical hyperemesis, and compulsive hot bathing.⁴

The syndrome has 3 phases. In the prodromal phase the patient has morning predominance of nausea, usually without emesis. This is followed by the hyperemesis phase, which is characterized by hyperemesis, vague abdominal pain, and learned compulsive hot bathing.

The third phase is the recovery phase, which is a return to normal behavior. During the recovery phase, if patients cease marijuana use, they remain asymptomatic; however, if patients continue to use marijuana, they often have recurrence of the hyperemesis phase.⁵ The diagnosis of cannabinoid hyperemesis syndrome is difficult as it is a diagnosis of exclusion. Patients may present to the ED many times prior to diagnosis. With the changing climate of marijuana laws, it is an important condition to consider when establishing a differential. More studies will be required to evaluate the overall prevalence of this condition as well as if there are any changes following the liberalization of marijuana laws in many states.