Sheila E. Crowe, MD, FRCPC, FACP, FACG, AGAF Department of Medicine University of California, San Diego

Transcription

1

2

3 Severe and Emergency Presentations of Celiac Disease Sheila E. Crowe, MD, FRCPC, FACP, FACG, AGAF Department of Medicine University of California, San Diego

4 Case Presentation (1) 63 year old male transferred for management of severe diarrhea to the University of Virginia from a hospital in West Virginia Hospitalized 3 times for hypotension, renal insufficiency, hypokalemia Past medical history significant for hypertension, inguinal hernia repair Reported diarrhea, weight loss and weakness over 4 months

5 Case Presentation (2) All of the following tests were normal Complete blood count Chemistry panel apart from low K, elevated creatinine and BUN Thyroid function tests Stool studies for infectious pathogens CT scan of abdomen 3 colonoscopies, one with biopsies EGD performed at UVA showed changes of celiac disease

6 Case Presentation (3) Started on a gluten free diet and prednisone slowly tapered Discharged home Recurrent severe diarrhea that led to dehydration and low potassium Required re-hospitalization, steroid therapy initiated Started on thiopurine treatment Eventually stabilized and maintained on 6-MP

7 Celiac Disease Crisis Acute onset of severe dehydration, renal dysfunction, electrolyte disturbance and weight loss Can be the initial presentation of celiac disease Can complicate refractory CD or CD with lymphoma Requires hospitalization, IV fluids, often requires steroid therapy, sometimes TPN One case series of 11 patients reported from Beth Israel-Deaconess Hospital All had Marsh 3 stage enteropathy, 1/3 with TVA Jamma, S, Leffler, DA, & colleagues, Clin Gastro & Hepatol, 8:587, 2010

8 Non-responsive Celiac Disease Usually due to ongoing or recurrent gluten exposure Coincident disorders Lactose intolerance Pancreatic insufficiency Small intestinal bacterial overgrowth Microscopic colitis IBS Unrelated to celiac disease incorrect or additional diagnoses Complications of celiac disease Refractory celiac disease Malignancy Krauss, GI Endosc Clin NA, 16: 317, 2006 Leffler, DA, et al. Clin Gastro & Hepatol, 5:445, 2007

9 Celiac Disease and Lactose Intolerance Constitutional lactase insufficiency Usually present before diagnosis of CD but may become more evident with intestinal damage Very common in native NA, Asians, Africans, and those from Mediterranean areas Secondary lactase insufficiency Gastroenteritis, Crohn s disease, celiac disease A common cause of lactose intolerance in CD Resolves on a GFD

10 Celiac Disease and Microscopic Colitis Retrospective study of 1009 patients with CD seen between 1981 and 2006; compared to a general population with microscopic colitis (MC) 44 (4.3%) of study population had MC Patients with CD & MC were older and had more severe villous atrophy Relative to diagnosis of CD, diagnosis of MC made after in 64%, at time of in 25% and before in 11% 2/3 required steroids or immunosuppressive therapies to control diarrhea In 16% colitis limited to the right colon Green, P et al, Clin Gastro & Hepatology, 7:1210, 2009

11 Non-responsive CD: King s College London Review of cases of NRCD over 18 months 112 patients referred with NRCD 12 did not have CD Of the 100 with CD, 45% non-compliant with GFD (53% inadvertent) 12% microscopic colitis 9% SIBO 9% RCD 3 had lymphoma After 2 years, 78 were well, 8 had continuing symptoms, 4 had died Dewar, DH, et al. W J Gastroenterol 18: 1348; 2012

12 Evaluation of Non-responsive CD Confirm the original diagnosis of CD Thoroughly review diet and medications for sources of gluten Evaluate and treat for lactose intolerance, pancreatic insufficiency, SIBO and microscopic colitis Assess for complicated CD (ulcerative, collagenous, strictures, malignancy) Determine if clonal IEL (T cells) are present by immunohistochemistry (ICH), flow cytometry and/or PCR studies of duodenal biopsies Rubio-Tapia & Murray, Gut, 59: 547, 2010

13 Non-responsive CD at UVA Review of cases on NRCD at UVA in past 10 yrs 272 with CD (69% F, 96% white) 97 of the 272 had NRCD 32% non-compliance with GFD 21% had IBS 10% microscopic colitis 5% gastroparesis 4% SIBO 3% pancreatic insufficiency 13% RCD Basile. JM, Hammerle, CW, Crowe, SE. DDW 2011

14 Refractory Celiac Disease (RCD) Villous atrophy associated with persistent or recurrent malabsorptive symptoms despite strict adherence to a GFD for at least 6-12 months in the absence of other causes of nonresponsive CD or overt malignancy Rare, prevalence low even in major referral centers Primary form no initial response to GFD Secondary form (more common) - after an initial period of response no longer responds to GFD ttg IgA often normal in RCD if patient is GF Rubio-Tapia & Murray, Gut, 59: 547, 2010

15 Refractory Celiac Disease Variants - collagenous, ulcerative, stricturing Risks for RCD: Older age, two DQ2 alleles Two main forms based on T cell TCR: RCD type I phenotypically normal IEL RCD type II associated with clonal expansion of IEL bearing CD3ε but lacking expression of CD4, CD8 and the β-chain of TCR Rubio-Tapia & Murray, Gut, 59: 547, 2010

16 Differential Diagnosis of RCD Adult-onset autoimmune enteropathy CVID Anti-epithelial antibodies (enterocyte, goblet cell) Absent plasma cells on biopsy, reduced serum Ig Tropical sprue Collagenous sprue Eosinophilic gastroenteritis Crohn disease Rubio-Tapa & Murray, Gut, 59: 547, 2010 Malamut, Am J Gastroenterol, 2010 in press

17 Study of Non-celiac Enteropathy Reviewed all cases of duodenal villous atrophy 30 cases of non-celiac enteropathy (NCE) 24 of these were HLA DQ2/DQ8 negative 26 negative for TTG IgA 10 had no increased IEL 21 misdiagnosed as CD, 1 gluten intolerance - no response to a GFD, no biopsy improvement Most common diagnosis was unspecified immune enteropathy (10) Pallav, K. Leffler, DA, et al, APT, 35: 380, 2012

18

19 Refractory Celiac Disease Prognosis Poor prognosis 50% of RCD type II die within 3 to 10 years usually due to: Lymphoma, intractable diarrhea, severe infections 5 yr survival rates for RCD II % Better prognosis for RCD I but higher mortality than uncomplicated CD AGA Technical Review, Gastroenterology, 131:1981, 2006 Cellier, Clin Gastro & Hepatol, 4: 1320, 2006

20 RCD Study from France Retrospective review, France: 14 patients with RCD I, 43 with RCD II Predictive factors of overt lymphoma and survival were studied in univariate and multivariate analyses At diagnosis, malnutrition, ulcerative jejunitis, and lymphocytic gastritis were more common in patients with RCD II than RCD I (P<.05) Overt lymphomas occurred in 2 patients with RCD I and 16 with RCD II Malamut, e al, Gastroenterology, 136: 81, 2009

21 RCD Study from France (2) Abnormal IEL phenotype and increased age at diagnosis of RCD were predictive factors for overt lymphoma by univariate analysis Abnormal IEL phenotype (P<.01), clonality (P=.01), and overt lymphoma (P=.001) predicted short survival time Only abnormal IEL phenotype (P=.03) and overt lymphoma (P=.04) were predictive in the multivariate analysis The 5-year survival rate was 93% in patients with RCD I and 44% with RCD II Malamut, et al, Gastroenterology, 136: 81, 2009

22 RCD Study from Mayo Clinic 57 patients with RCD: 42 RCD I, 15 RCD II 15 of 57 patients died during follow-up (8/42 RCD I, 7/15 RCD II) within the first 2 years after RCD diagnosis Overall 5-year cumulative survival was 70% (entire cohort), 80% (RCD I), and 45% (RCD II) The refractory state itself and EATL were the most common causes of death A poorer prognosis predicted by age 65 yr, albumin 3.2 g/dl, Hgb 11 g/dl, and total villous atrophy Rubio-Tapa, A, Gastroenterology, 136: 99, 2009

23 RCD Beth Israel Deaconess 34 of 844 with CD (4.0%) had RCD Only 5 with RCD II, 2 died of EATL within 24 mo Unintentional weight loss 76.5% (RCD) vs 16.7% CD Diarrhea at diagnosis 79.4% RCD vs 40.5% CD Authors speculated that RCD is more severe in Europe versus North America Roshan, B, Leffler, DA, et al, Am. J. Gastroenterol, 106: 923, 2011 Malamut, G, Cellier, C, Am. J. Gastroenterol, 106: 929, 2011

24 Experience with RCD at UVA 19 of 97 with NRCD had RCD (20%) 3 type I 14 type II 2 untyped All had evidence of malabsorption 17 (89%) received steroids, 14 (74%) thiopurines 11 received temporary enteral and/or parenteral nutrition 2 died of celiac disease associated process EATCL Inflammatory neurological disorder Basile. JM, Hammerle, CW, Crowe, SE. DDW 2011

25 Take Home Messages Multiple causes of nonresponsive celiac disease Continued gluten ingestion is the major cause A small subset are due to refractory celiac disease Consider other causes of an enteropathy that does not respond to a truly gluten-free diet Celiac disease crisis is rare but requires prompt recognition and supportive management

26

27