A Rare Case of Hyponatremia and Gallbladder Cancer.

Question: A 54-year-old woman with a history of diabetes and hypertension, presented to our hospital with jaundice, nausea, and intense fatigue for 1 month. She denied any abdominal pain, recent medication changes, or sick contacts. On presentation, her laboratory tests were significant for severe hyponatremia of 114 mEq/L, hypokalemia of 2.9 mEq/L, and hypochloremia of 79 mEq/L. Serum glucose was 157 mg/dL, blood urea nitrogen was 44 mg/dL, and serum creatinine was 1.79 mg/dL. Liver biochemistries were as follows: aspartate transaminase 105 IU/L, alanine transaminase 59 IU/L, total bilirubin 26.6 mg/dL, and alkaline phosphatase 1966 IU/L. She also showed mild hypoalbuminemia (2.6 g/dL) and elevated platelet count of 697/microliter. Contrast-enhanced computed tomography revealed a severely distended gallbladder with a soft tissue mass suggestive of gallbladder cancer. There was marked intrahepatic ductal dilation secondary to biliary obstruction in the region of the duodenum due to lymphadenopathy (Figure A). The pancreas was unremarkable. How do you prepare this patient for endoscopic retrograde cholangiopancreatography (ERCP), given her severe hyponatremia? See the Gastroenterology website (www.gastrojournal.org) for more information on submitting to Gastro Curbside Consults Hyponatremia is the measure of total water imbalance relative to plasma electrolytes such as sodium and potassium. The first test in the evaluation of hyponatremia should be the measurement of serum osmolality, which can differentiate true hyponatremia from pseudo-hyponatremia. In this case, the serum osmolality was normal (285 mmol/kg), thus confirming the diagnosis of pseudo-hyponatremia. Pseudo-hyponatremia is an artefactual result due to the way the blood sample is processed. Most laboratories use indirect ion-selective electrode (ISE) potentiometry to measure serum electrolyte levels, which includes diluting the serum. The accuracy of indirect ISE sodium measurement depends on the assumption that the volume of serum or plasma occupied by water is ∼93% and the remaining ∼7% is occupied by lipids and proteins. Indirect ISE sodium measurement can give rise to spuriously decreased serum/plasma sodium concentration (pseudo-hyponatremia) if lipids and/or protein are significantly raised, because under these circumstances the non-water fraction is >7% and the water fraction is <93%, so the diluted sample presented to the electrode contains fewer sodium ions than would be the case if the sample had normal proportion of water (93%). The cause of the pseudo-hyponatremia in this patient was the accumulation of lipoprotein X (LPX) in the serum as a result of obstructive jaundice. Patients with biliary obstruction can present with hyponatremia due to various etiologies. Measurement of serum osmolality and assessment of plasma volume status can differentiate hypovolemic hyponatremia (in cases with dehydration, infection, etc), euvolemic hyponatremia (associated endocrine disorders such as adrenal insufficiency and hypothyroidism), hypervolemic hyponatremia (especially with concomitant cirrhosis or heart failure), and pseudo-hyponatremia (as in the present case). True hyponatremia is treated with repletion of sodium with a solute that has a higher osmolality than the urine osmolality in cases of hypovolemia. In patient with hypervolemia or euvolemia, water restriction or use of diuretics may be useful. Pseudo-hyponatremia can be seen in states of excess fat (hyper-triglyceridemia) or protein deposition (multiple myeloma) in the plasma that account for the spurious result and needs no corrective measures for the sodium itself but rather needs treatment for the underlying cause. LPX has molecular structure similar to low-density lipoprotein (LDL).1Brandt E.J. Regnier S.M. Leung E.K. et al.Management of lipoprotein X and its complications in a patient with primary sclerosing cholangitis.Clin Lipidol. 2015; 10: 305-312Crossref PubMed Scopus (14) Google Scholar With severe cholestasis, biliary lipoprotein escapes to the plasma pool and binds to albumin to form LPX. In the present patient, LPX made up the majority of the LDL portion. Her total cholesterol was 1059 mg/dL, high-density lipoprotein was 34 mg/dL, and triglyceride was 290 mg/dL; the gap accounts for LPX accumulation.2Heimerl S. Boettcher A. Kaul H. Liebisch G. Lipid profiling of lipoprotein X: implications for dyslipidemia in cholestasis.Biochim Biophys Acta. 2016; 1861: 681-687Crossref PubMed Scopus (14) Google Scholar Treatment is directed at relieving the biliary obstruction if possible and medical therapy with cholesterol medications and bile acid sequestrants. Cholestatic liver diseases, including but not limited to primary biliary cholangitis, primary sclerosing cholangitis, and less commonly jaundice from mechanical obstruction (eg, pancreatobiliary cancer) are also known to be associated with LPX elevations. Therefore, it should be noted that severe cholesterol elevations in these conditions can result in artefactual electrolyte abnormalities, including pseudo-hyponatremia, hypokalemia, and hypochloremia. Because the serum sodium level was not itself a contraindication, ERCP was performed and revealed the presence of an anomalous pancreatic biliary junction (APBJ) and a mid-common bile duct stricture (Figure B). A 10-F × 15-cm biliary plastic stent was placed. Endoscopic ultrasound with biopsy of the gall bladder mass confirmed this to be an adenocarcinoma. Besides biliary stenting, the patient was started on 4 g cholestyramine twice a day and 300 mg ursodiol twice a day. She was discharged in 2 weeks with a sodium level of 132 mEq/L, total bilirubin of 6.7 mg/dL, and alkaline phosphatase of 373 IU/L. Gallbladder cancer is rare, with rates of 1.4 per 100,000 among women and 0.8 among men.3Rawla P. Sunkara T. Thandra K.C. Barsouk A. Epidemiology of gallbladder cancer.Clin Exp Hepatol. 2019; 5: 93-102Crossref PubMed Scopus (109) Google Scholar Traditional risk factors are obesity, presence of gallstones, gallbladder polyps, primary sclerosing cholangitis, and porcelain gallbladder. APBJ can be associated with type I choledochal cyst, and those patients are at risk for bile duct cancer (cholangiocarcinoma). Surgical resection of the extra-hepatic biliary tree (bile duct and gallbladder) should be considered. APBJ without the presence of type I choledochal cyst is very uncommon but important to recognize, because those patients are at risk for gallbladder cancer. Therefore, prophylactic cholecystectomy is typically recommended. The present patient had least stage IIIB gallbladder cancer that was deemed to be surgically nonresectable. Therefore, she was started on chemotherapy with cisplatin and gemcitabine along with immunotherapy (durvalumab). In conclusion, pseudo-hyponatremia could be seen in cases of severe biliary obstruction due to accumulation of LPX and can mimic other etiologies of true critical hyponatremia. Being aware of the use of serum osmolality and the patient’s volume status to differentiate these two entities would avoid unnecessary delay in the patient’s care.