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Vitamin B12 Deficiency in Patients With Unexplained Portal Hypertension Indicates Absence of Severe Liver Fibrosis.

To the Editor: We read with interest the review on noninvasive markers of liver fibrosis.1 We concur that widespread availability of vitamin B12 testing makes it an attractive noninvasive marker of liver fibrosis. Although the authors focused on higher serum vitamin B12 to test for cirrhosis (ie, severe liver fibrosis), we wish to highlight the opposite role: vitamin B12 deficiency indicates absence of severe liver fibrosis in patients with unexplained portal hypertension. Noncirrhotic intrahepatic portal hypertension (NCIPH), a chronic microangiopathy of portal vein radicles, mimics cryptogenic cirrhosis on clinical and laboratory/imaging parameters. Even the gross appearance of the liver can mimic cirrhosis.2 In India, the combination of endemic vitamin B12 deficiency (upto 60% of population maybe deficient)3 and NCIPH being a significant cause of portal hypertension4,5 provides an unique opportunity to see whether lower serum vitamin B12 levels are associated with lesser degrees of liver fibrosis in patients with unexplained portal hypertension. We have previously demonstrated utility of serum vitamin B12 level to differentiate NCIPH from cryptogenic cirrhosis.6 As we had not specifically compared serum vitamin B12 level with degree of liver fibrosis on histology in the previous study, we herewith present reanalysis of the previous study data. As the normal range for serum vitamin B12 level was 200 to 950pg/mL, we defined patients with serum vitamin B12 levels of <200pg/mL as vitamin B12 deficient. For this analysis, we included patients with serum vitamin B12 assayed at baseline, that is, 42 NCIPH patients (age: median=28y; range, 7 to 59y;male: 25; Child’s score: 5; range, 5 to 9; esophageal varices: large, 31; small, 11) and 38 cryptogenic cirrhosis patients (age: median=49y; range, 16 to 67y; male: 31; Child’s score: 6; range, 5 to 10; esophageal varices: large, 27; small,11). Liver biopsy was done in all study patients and route of biopsy was transjugular in 29 patients, percutaneous in 10, peroperative in 2, explant in 1 in NCIPH patients and transjugular in 30, percutaneous in 8 in cryptogenic cirrhosis patients. Three (1 to 8) [median (range)] cores of liver tissue were obtained with 10 (5 to 20) portal tracts in biopsy specimen in NCIPH patients. All the biopsies were routinely stained with hematoxylin-eosin, reticulin, orcein, van-Gieson, periodic acid with and without diastase, and Perl’s Prussian blue stains. Masson’s trichrome was used when required. Cirrhosis was present in 38 cases. In NCIPH group, degree of fibrosis was classified as no fibrosis (12), mild portal/ periportal fibrosis (28), and moderate portal/periportal fibrosis with occasional septa formation (2).7 In addition, mild perisinusoidal fibrosis was noted in 15 patients. Serum vitamin B12 levels were significantly lower in NCIPH patients with lesser degree of portal/periportal liver fibrosis [no liver fibrosis: serum B12 level [median (range)] 304 (182 to 944)pg/mL; mild fibrosis: 299 (107 to 1419)pg/mL, moderate fibrosis: 490 (389 to 591)pg/mL] compared with cirrhosis patients: 723 (209 to 2000) pg/mL (P<0.001) (Fig. 1). Vitamin B12 deficiency was noted in 9 of 42 NCIPH patients (no liver fibrosis: 2, mild fibrosis: 7, moderate fibrosis: 0) as compared with none of 38 patients with cirrhosis (odds ratio=infinity; 95% CI, 1.8-infinity; positive predictive value= 100%, specificity=100%). ROC curve depicted usefulness of low serum vitamin B12 as a marker of either no liver fibrosis or only mild liver fibrosis in study patients (AUROC=0.84; 95% CI, 0.76-0.93). Small number of patients studied is a limitation of our study. Endemic vitamin B12 deficiency, possibly due to inadequate dietary intake,3 makes this a useful noninvasive biomarker to rule out severe liver fibrosis in India. Indeed, the clinical context appears to be important in applying noninvasive biomarkers for liver fibrosis.8