potassium concentration below 1.5Ð2.0 meq/L due to concurrent urinary potassium wasting.

Muscle paralysis and respiratory arrest have been reported as consequences of the severe hypokalemia [40]; in some cases, hypokalemic paralysis has been the presenting symptom of SjšgrenÕs syndrome [41].

The mechanism by which SjšgrenÕs syndrome leads to type 1 RTA is incompletely understood. A possible mechanism is the presence of high titers of an autoantibody directed against carbonic anhydrase II; inhibition of this enzyme would result in the generation within the cell of fewer hydrogen ions available for secretion.

Nephrogenic diabetes insipidus [42, 43]Ñ Polyuria and polydipsia due to nephrogenic diabetes insipidus are other manifestations of impaired tubular function in SjšgrenÕs syndrome. Once again, patients may present with these complaints rather than a sicca syndrome. It is, therefore, important to exclude SjšgrenÕs syndrome in any adult with symptomatic nephrogenic diabetes insipidus who does not have the two most common causes of this disorderÑchronic lithium ingestion or hypercalcemia.

Hypokalemia without renal tubular acidosis [44]ÑThe tubular injury induced by the interstitial nephritis indirectly leads to potassium wasting and potentially severe hypokalemia. The primary defect is thought to be sodium wasting, which has two effects that augment potassium secretion: it increases sodium delivery to the potassium secretory site in the collecting tubules and, via volume depletion, enhances the release of aldosterone. The use of spironolactone may be helpful in these patients.

18.5.1.1 Glomerular Disease

Glomerular involvement is much less common than interstitial nephritis in SjšgrenÕs syndrome [45, 46]. Membranoproliferative glomerulonephritis and membranous nephropathy are the most common. The pathogenesis of the glomerular disease, including the possible etiologic relationship to SjšgrenÕs syndrome, is unclear, but may be related to the deposition of circulating immune complexes. Other etiologies are mixed cryoglobulinemia and amyloid. Optimal

therapy is uncertain. Some patients with membranoproliferative glomerulonephritis, for example, have been treated with prednisone without or with cytotoxic therapy (such as cyclophosphamide) with varying success; in one case, spontaneous remission occurred. As in SLE patients, mycophenolic acid is being used to treat SS glomerulonephritis as an alternative to cyclophosphamide. Azathioprine has also been used as a steroid-sparing drug in patients with glomerulonephritis.

In patients with glomerulonephritis due to mixed cryoglobulinemia, plasmapheresis, and cytotoxic therapy may be required [47].

18.6Gastrointestinal Manifestations

18.6.1 Mesenteric Vasculitis

Mesenteric vasculitis may occur in SS patients, similar to patients with SLE in the setting of a generalized vasculitis [48]. The vasculitis associated with SS or systemic lupus erythematosus (SLE) involves small-sized and medium-sized vessels and involves the gastrointestinal tract. Lower abdominal pain secondary to mesenteric vasculitis is generally an insidious symptom that may be intermittent for months prior to the development of an acute abdomen with nausea, vomiting, diarrhea, GI bleeding, and fever [49]. Risk factors for the development of mesenteric vasculitis include peripheral vasculitis and central nervous system vasculitis. Patients with an acute presentation may also have mesenteric thrombosis and infarction often in association with anti-phospholipid antibodies.

Mesenteric vasculitis is a potentially lifethreatening disorder. In addition to the possible development of necrotic segments of bowel, patients may suffer septic complications and bowel perforation. Current therapy of severe SS vasculitis is more aggressive and typically consists of intravenous pulse methylprednisolone and pulse cyclophosphamide [50].

These patients can also present acutely with small bowel obstruction secondary to strictures,

resembling CrohnÕs disease or intussusception, or with massive gastrointestinal bleeding secondary to aneurysm formation. Bowel infarction, perforation, and peritonitis are rare complications of chronic intestinal ischemia due to vasculitis [50].

In addition to mesenteric ischemia, systemic vasculitis can also cause ischemic hepatitis, pancreatitis, cholecystitis, and less commonly gastritis or esophagitis. Treatment of mesenteric vasculitis in SS is similar to that used in polyarteritis nodosa with corticosteroids and cyclophosphamide, which has led to a dramatic improvement in patient survival and relief of symptoms [49].

The differential diagnosis should include HenochÐSchšnlein purpura (HSP), which is a small vessel vasculitis that typically occurs in children, although all ages can be affected. Patients classically exhibit lower extremity purpura, arthritis, and hematuria, which can all be mistaken for vasculitis in the setting of SS.

18.6.2 Primary Biliary Cirrhosis

Primary biliary cirrhosis patients have a high frequency of sicca complaints and, due to their frequently positive anti-nuclear antibody (ANA), may be labeled as SS patients [51, 52]. In some studies there is an increased frequency of overlap PBC-associated autoantibodies (antimitochondrial antibody) and those antibodies found in SS patients. Primary biliary cirrhosis (PBC) is characterized by an ongoing immunologic attack on the intralobular bile ducts that eventually leads to cirrhosis and liver failure.

There are a number of complications that occur in PBC that require therapy. These include the following:

¥Pruritis associated with bile salts

¥Metabolic bone disease

¥Hypercholesterolemia and xanthomas

¥Malabsorption vitamin deÞciencies

¥Hypothyroidism anemia

The role of immunosuppressive drugs remains

unproven, although ursodeoxycholic acid has been shown to halt disease progression [53]. Colchicine has also been reported as helpful [54].

Symptomatic steatorrhea due to bile acid insufÞciency can be partially corrected by restricting dietary fat. Medium-chain triglycerides (MCTs) can be added if caloric supplementation is required to maintain body weight. The digestion and absorption of MCTs are not nearly as dependent upon bile acids as are the long-chain fatty acids, which are the major constituent of dietary triglycerides. Each milliliter of MCT oil contains 7.5 calories. Most patients can tolerate 60 mL/day without difÞculty. MCT oil can be taken directly by the teaspoon or can be used as salad oil or as a substitute for shortening in cooking.

If pancreatic insufÞciency is suspected, it is easier to treat with pancreatic enzyme replacement than it is to diagnose. Preparations such as Pancrease and pancrelipase (Creon) taken with meals are usually effective.

DeÞciencies of fat-soluble vitaminsÑPatients with PBC may have malabsorption of the fatsoluble vitamins A, D, E, and K. DeÞciencies of vitamin E are uncommon except in patients with advanced disease awaiting liver transplantation. In comparison, vitamin A deÞciency occurs in approximately 30% of patients but is rarely symptomatic. It correlates directly with serum retinol-binding protein and albumin levels and inversely with serum bilirubin levels. Vitamin A deÞciency usually responds to dietary supplements of vitamin A, 15,000 units/day (three times the recommended daily allowance). In exceptional cases, as in the patient with night blindness, parenteral vitamin A may be required.

Vitamin D deÞciency, if untreated, can lead to osteomalacia. It is best detected by measuring the serum concentration of calcitriol (25-hydroxyvitamin D), the metabolite of vitamin D produced in the liver. Serum levels of vitamin D and calcitriol (the most active form of vitamin D) are usually normal in PBC except for patients who are deeply jaundiced and who are candidates for liver transplantation.

Annual measurement of serum vitamin A and calcidiol levels is sufÞcient in patients whose serum bilirubin concentration is elevated. Less frequent measurements, e.g., every 2Ð3 years, is sufÞcient in patients with normal serum bilirubin

levels. Measurements should be obtained more frequently in patients whose values are just above the lower limit of normal.

Clinically important vitamin K deÞciency rarely occurs in PBC unless the patient regularly takes cholestyramine and is deeply jaundiced. The prothrombin time is normal in most patients until late in the course of the disease when there are signs of liver failure. Only these patients require vitamin K supplementation.

Celiac Sprue [55]ÑSerologic studies are now used to further conÞrm the diagnosis of celiac disease. These include the ELISA for IgA antibodies to gliadin and the immunoßuorescence test for IgA antibodies to endomysium, a structure of the smooth muscle connective tissue, the presence of which is virtually pathognomonic for celiac disease. Using these methods, the incidence of celiac sprue is elevated in SS patients [56]. Treatment includes avoidance of gluten as well as attention to the consequences of malabsorption that are similar to the nutrient and vitamin deÞciencies described above.

Gastroparesis [57] is deÞned as delayed gastric emptying, and patients often complain of bloating. Its true prevalence in SS is unknown; however, it is estimated that up to 20% of SS patients may have some slowing of gastric motility. Concurrent lactose intolerance also may play a role. SS patients should be cautious in prolonged use of this drug since a recent analysis suggested that metoclopramide is the most common cause of drug-induced movement disorders. Another analysis of study data by the FDA showed that about 20% of patients in that study that used metoclopramide took it for longer than 3 months. The FDA only approves metoclopramide for 4- to 12-week short-term treatment.

Domperidone (trade names Motilium, Motillium, Motinorm, and Costi) is an antidopaminergic drug used as a prokinetic agent used in Canada and Europe [58]. Higher acetylcholine levels increase gastrointestinal peristalsis and further increase pressure on the lower esophageal sphincter, thereby stimulating gastrointestinal motility, accelerating gastric emptying, and improving gastro-duodenal coordination. It should be noted

that the FDA turned down an application for domperidone in the USA, even though the FDAÕs division of gastrointestinal drugs had approved domperidone. Individual incidents of problems with the drug include cardiac arrhythmia and potential interaction with other medications has been reported.

The association between delayed gastric emptying and SS is not straightforward. Delayed gastric emptying is present in 25Ð40% of patients with functional dyspepsia, a condition affecting approximately 20% of Western population with increased frequency in patients with Þbromyalgia.

In addition, the magnitude of the delay in gastric emptying is often modest and not well correlated with symptoms, except possibly bloating. One possible explanation for the poor correlation between delayed gastric emptying and symptoms in SS may be involvement of the afferent sensory nerve Þbers by autonomic neuropathy thereby decreasing perception of symptoms.

Also, bloating is a common symptom in SS patients and may be due to the increased amount of air swallowed with food due to their dysphagia as a result of decreased saliva. Concurrent lactose intolerance also may play a role in non-speciÞc gastrointestinal symptoms. It is estimated that 75% of adults worldwide show some decrease in lactase activity during adulthood, although there is no clear evidence for an increased frequency in SS patients. Due to difÞculty in swallowing other solid foods, the diet in SS patients may be skewed toward Òsofter foodsÓ including milk and derived products such as yogurt. The frequency of decreased lactase activity ranges from as little as 5% in northern Europe, up to 71% for Sicily, to more than 90% in some African and Asian countries. Disaccharides cannot be absorbed through the wall of the small intestine into the bloodstream, so in the absence of lactase, lactose present in ingested dairy products remains uncleaved and passes intact into the colon. The operons of enteric bacteria quickly switch over to lactose metabolism, and the resulting in vivo fermentation produces copious amounts of gas (a mixture of hydrogen, carbon