Celiac Disease: Beyond Bowels, Blood, & Bones

Celiac Disease: Beyond Bowels, Blood & Bones Patricia Raymond MD FACP FACG

Objectives
Identify the prevalence of celiac disease, nationally and worldwide
Summarize what is known about the pathophysiology of the disease
Describe the comorbitities found with celiac disease
Explain the limitations of conventional management and advances in the future

Prevalence in the US
Healthy Individuals 1:133
Symptomatic Subjects 1:40
1 st Degree Relative with Celiac 1:22
2 nd Degree Relative with Celiac 1:39
Projected number Celiacs in US 2,115,954
Known Celiacs in US 40,000
For each known Celiac, there are 53 undiagnosed patients
Arch Int Med 2003; 163: 286-292

Celiac Disease Globally Prevalence on Screening Data http://www.istockphoto.com/janrysavy Worldwide 1:266 Brazil 1:400 Denmark 1:500 Finland 1:130 Germany 1:500 Italy 1:184 Netherlands 1:198 Norway 1:250 Sahara 1:70 Sweden 1:190 United Kingdom 1:112 USA 1:133

Objectives

Pathophysiology
Allergy to the protein ‘gluten’, found in wheat, rye, barley
Leads to lymphocytic infiltrate in small intestinal mucosa, villous atrophy
Diagnosis
History
Serology
Endoscopic gross appearance
Endoscopic biopsy
Treatment is “only” GFD
http://www.aafp.org/afp/20071215/1795.html

Bowels , Blood, and Bone
Diarrhea
From 45-85% of patients
Diarrhea persisting despite GFD
Microscopic colitis
Steatorrhea secondary to pancreatic exocrine insufficiency
Secondary lactose or fructose malabsorption
Anal sphincter dysfunction causing fecal incontinence
Irritable bowel syndrome
Small bowel bacterial overgrowth
Constipation
due to low fiber intake with avoidance of common whole grains
responds to dietary rice bran and ispaghula husks (psyllium)

Bowels, Blood , and Bone
Anemia
10-15% of celiac patients
Due to impaired absorption of iron and/or folate from the proximal small intestine.
In celiac disease with ileal involvement
Impaired absorption of vitamin B-12
Macrocytic anemia, elevated MCV
Who has the highest yields on small bowel biopsy?
6- 12% of iron deficient patients have celiac disease
20% of nonresponders to supplemental iron have celiac disease
www.istockphoto.com/vladm

Bowels, Blood, and Bone
Osteopenia, rarely osteoporosis.
Due to secondary hyperparathyroidism, likely from due to vitamin D deficiency
Partial reversal with a gluten-free diet
Peripheral bone loss may persist despite normalization at axial skeletal sites
Advanced disease may have bone pain,
pseudofractures, or deformity
May occur without gastrointestinal symptoms
Most patients are asymptomatic or have only raised serum levels of alkaline phosphatase or hypocalcemia
Evaluation of people with celiac
Baseline DEXA (dual energy x-ray absorptiometry) scan
Repeat DEXA scan after one year
www.istockphoto.com DoctorKan

Objectives

CAUTION needed!
Case reports and small series
Many international, not directly applicable to US population
Do not assume causal
In some cases, but not all, comorbidity improves with GFD
Recognition of celiac comorbidities may lead to diagnosis
Time from symptom onset to diagnosis in US as long as 10 years
There’s a lot to celiac disease beyond bowels, blood, and bones http://www.istockphoto.com/LajosRepasi C L E I A C

Depression
60% vs 10% controls
Anxiety
62% vs 31% controls
Epilepsy
1 in 44
Advocate celiac screen in all epileptics
Neuropathy
Sensory or motor neuropathies
Check for celiac in unexplained advocated
Cerebral http://www.istockphoto.com/hidesy C L E I A C

Gluten ataxia
Small series of 28 patients found to have celiac disease
Gait and some limb ataxia, 19 with peripheral neuropathy
16 of 28 without bowel symptoms
Cognitive impairment in elderly
Newly diagnosed celiac disease
Dementia responsive to GFD
Episodic headache
Down syndrome
Prevalence of biopsy proven celiac disease up to 16 %
20-fold increase compared to the general population
Cerebral http://www.istockphoto.com/mpabild C L E I A C

Autoimmune myocarditis and idiopathic dilated cardiomyopathy
5 percent of patients with autoimmune myocarditis or idiopathic dilated cardiomyopathy have celiac disease
In one report of nine patients, none had classic GI symptoms of celiac disease (recurrent abdominal pain, diarrhea, and weight loss), but all had iron deficiency anemia refractory to oral iron replacement
Cardiac function improved with GFD +/- immunosuppressive therapy.
Cardiac www.istockphotp.com/dny59i C L E I A C

Cutaneous
Dermatitis Herpetiformis
95% extensor elbows
66% buttocks
Also at extensor knees, sites of clothing pressure (belt, bra)
2/3 have celiac disease
Likely all have some degree gluten sensitivity
Rapid response to dapsone, slow response to GFD
http://www.nlm.nih.gov/medlineplus/ency/imagepages/2791.htm C L E I A C

Atrophic glossitis
Erythema or atrophy
Soreness or burning sensation of the tongue
Responds to gluten free diet
Ask your dentist!
71/128 (55%) with celiac disease have oral aphthous ulcers or dental enamel ‘pits’
Cutaneous www.istockphoto.com/shironosov C L E I A C

Diabetes mellitus type 1
2.6 % have EMA IgA and 7.8 % have TTG IgA
Most positive patients will have positive small bowel biopsy for celiac disease
3.5 % of children of parents with type 1 diabetes have celiac disease, prevalence increases with age
Human studies unclear on GFD & modulation of diabetes
Animal studies suggest that the interplay between gluten exposure and the intestinal immune system can modulate the development of type 1 diabetes
Endocrine www.istockphoto.com/laures C L E I A C

Autoimmune thyroid disease
14% of people with celiac
Hypothyroidism 10%
Hyperthyroidism 4%
Pancreatitis
Celiac disease patients have
3.3 HR (Hazard Risk) pancreatitis of all kinds
19.8 HR chronic pancreatitis
Risk of subsequent diagnosis of celiac disease
Pancreatitis of any type (OR 3.2)
Chronic pancreatitis (OR 7.3.)
Endocrine www.istock.com/angelhell C L E I A C

Kidney disease
Glomerular IgA deposition is common
Occurs in up to 33%
Most with no clinical manifestations of renal disease
Felt to be because of no associated activation of complement
Elimination (Kidney) www.istockphoto.com/eraxion C L E I A C

Elevated liver tests
Up to 40% adult patients with celiac
Nonspecific mild chronic elevation in serum aminotransferase levels
AST ranging from 29 to 80
ALT ranging from 60 to 130
ALT usually slightly greater than AST
Celiac disease accounts for 4 % of abnormal liver function tests of unexplained etiology
Liver Tests www.istockphoto.com/eraxion C L E I A C

Primary biliary cirrhosis
PBC in people with celiac 3%
Celiac disease in patients with PBC 6%
Primary sclerosing cholangitis
Celiac in 3% patients with PSC
Advanced liver disease
One report focused on four patients with severe liver disease (due to congenital liver fibrosis, massive steatosis, and progressive hepatitis of unclear origin) and untreated celiac disease. Hepatic dysfunction reversed in all patients following a gluten-free diet
Liver Tests http://www.istockphoto.com/eraxion C L E I A C

Idiopathic pulmonary hemosiderosis
Lane-Hamilton syndrome
Coexistence of celiac disease and idiopathic pulmonary hemosiderosis
Gluten-free diet has been associated with remission of pulmonary symptoms in several patients
Lungs www.istock.com/eraxion C L E I A C

Increased frequency of menstrual abnormalities
later menarche
earlier menopause
Infertility
Prevalence 1 in 96 with fertility problems
15% miscarriage vs 6% controls
IUGR
Threefold higher risk of intrauterine growth restriction among infants of mothers with undiagnosed celiac disease compared with controls
GFD prevents/corrects these issues
Infertility, female Females with untreated celiac disease C L E I A C

Infertility, male
Abnormalities in sperm motility and morphology
Androgen resistance
high serum testosterone and high LH concentrations
GFD led to normalization of the biochemical abnormalities and sperm
C L E I A C

Hyposplenism
Several case reports
Prophylactic pneumococcal vaccination has been suggested
Selective IgA deficiency
In up to 8 % of celiac patients
Compares with one in 500-700 control population
May render serologic testing inaccurate
Immune System C L E I A C

Osteoarthritis
26% patients
7.5% controls
Not very responsive to GFD
Arthritis www.istockphoto.com/aceshot C L E I A C

Risk of malignancy overstated
Standardized incidence ratio {SIR} 1.3
Suggests that the overall increase in cancer risk is modest
Lymphoma
Most common malignancy
SIR 5.9
Digestive tract cancers increased
including squamous cell esophagus, small intestinal, colorectal, and hepatocellular
Breast & lung reduced! Why?
Cancer www.istockphoto.com/eraxion C L E I A C

Cerebral
Cardiac
Cutaneous
Endocrine
Elimination (Kidney)
Liver
Lungs
Infertility
Immune System
Arthritis
Cancer
Pop quiz: CCCEELLIIAC? Name some associated comorbidities! C L E I A C

Objectives

Celiac now, and in the future?
How much flour is ‘gluten free’?
Oats have been removed from the forbidden list, but have they been processed in a gluten free environment?
Inconsistent labeling of processed foods
How do you eat out at restaurants or friends’ homes?
Find the hidden gluten
www.istockphoto.com/snokid

Research is underway to change the future of celiac disease
Enzyme therapy (Stanford Chemical Engineering Dept) Two-enzyme cocktail detoxifies grocery store gluten within 10 minutes under simulated duodenal conditions
Probiotic therapy (VSL3)- decreased toxicity of gliadin in long term fermentation in test tube
Oral budesenide (locally active steroid) for RS (9 patients- 2 failed to respond
Encapsulated enzyme extract (based on animal digestive tract) (RMIT Melbourne) 21 CD challenged with gluten daily over 2 weeks. Reduced symptoms on enzyme vs placebo, no TTG increase

Objectives

References 1 of 4
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Hadjivassiliou, M, Chattopadhyay, AK, Davies-Jones, GA, et al. Neuromuscular disorder as a presenting feature of coeliac disease. J Neurol Neurosurg Psychiatry 1997; 63:770.
Cronin, CC, Jackson, LM, Feighery, C, et al. Coeliac disease and epilepsy. QJM 1998; 91:303.
Hu, WT, Murray, JA, Greenaway, MC, et al. Cognitive impairment and celiac disease. Arch Neurol 2006; 63:1440.
Hadjivassiliou, M, Grunewald, RA, Chattopadhyay, AK, et al. Clinical, radiological, neurophysiological, and neuropathological characteristics of gluten ataxia. Lancet 1998; 352:1582.
Hadjivassiliou, M, Grunewald, RA, Lawden, M, et al. Headache and CNS white matter abnormalities associated with gluten sensitivity. Neurology 2001; 56:385.
Hadjivassiliou, M, Maki, M, Sanders, DS, et al. Autoantibody targeting of brain and intestinal transglutaminase in gluten ataxia. Neurology 2006; 66:373.
Lubrano, E, Ciacci, C, Ames, PR, et al. The arthritis of coeliac disease: Prevalence and pattern in 200 adult patients. Br J Rheumatol 1996; 35:1314.
Ackerman, Z, Eliakim, R, Stalnikowica, R, Rachmilewitz, D. Role of small bowel biopsy in the endoscopic evaluation of adults with iron deficiency anemia. Am J Gastroenterol 1996; 91:2099.

References 2 of 4
Kemppainen, T, Kroger, H, Janatuinen, E, et al. Osteoporosis in adult patients with celiac disease. Bone 1999; 24:249.
Selby, PL, Davies, M, Adams, JE, Mawer, EB. Bone loss in celiac disease is related to secondary hyperparathyroidism. J Bone Miner Res 1999; 14:652.
West, J, Logan, RF, Card, TR, et al. Fracture risk in people with celiac disease: A population-based cohort study. Gastroenterology 2003; 125:429.
Carroccio, A, Giannitrapani, L, Di Prima, L, et al. Extreme thrombocytosis as a sign of coeliac disease in the elderly: case report. Eur J Gastroenterol Hepatol 2002; 14:897.
Nielsen, OH, Jacobsen, O, Pedersen, ER. Nontropical sprue: Malignant diseases and mortality rate. Scand J Gastroenterol 1985; 20:13.
Anderson, LA, McMillan, SA, Watson, RG, et al. Malignancy and mortality in a population-based cohort of patients with coeliac disease or'gluten sensitivity'. World J Gastroenterol 2007; 13:146.
Acerini, CL, Ahmed, ML, Ross, KM, et al. Coeliac disease in children and adolescents with IDDM: Clinical characteristics and response to gluten-free diet. Diabet Med 1998; 15:38.
Cronin, CC, Feighery, A, Ferriss, JB, et al. High prevalence of celiac disease among patients with insulin-dependent (type 1) diabetes mellitus. Am J Gastroenterol 1997; 92:2210.
Saukkonen, T, Savilahti, E, Reijonen, H, et al. Coeliac disease: frequent occurrence after clinical onset of insulin-dependent diabetes mellitus. Childhood Diabetes in Finland Study Group. Diabet Med 1996; 13:464.
Ziegler, AG, Schmid, S, Huber, D, et al. Early infant feeding and risk of developing type 1 diabetes-associated autoantibodies. JAMA 2003;290:1721.

References 3 of 4
Cataldo, F, Marino, V, Bottaro, G, et al. Celiac disease and selective immunoglobulin A deficiency. J Pediatr 1997; 131:306.
Bardella, MT, Vecchi, M, Conte, D, et al. Chronic unexplained hypertransaminasemia may be caused by occult celiac disease. Hepatology 1999; 29:654.
Abdo, A, Meddings, J, Swain, M. Liver abnormalities in celiac disease. Clin Gastroenterol Hepatol 2004; 2:107.
Kaukinen, K, Halme, L, Collin, P, et al. Celiac disease in patients with severe liver disease: Gluten-free diet may reverse hepatic failure. Gastroenterology 2002; 122:881.
Kingham, JG, Parker, DR. The association between primary biliary cirrhosis and coeliac disease: A study of relative prevalences. Gut 1998; 42:120.
Counsell, CE, Taha, A, Ruddell, WS. Coeliac disease and autoimmune thyroid disease. Gut 1994; 35:844.
Sher, KS, Mayberry, JF. Female fertility, obstetric and gynaecological history in coeliac disease: A case control study. Acta Paediatr Suppl 1996; 412:76.
Kolho, KL, Tiitinen, A, Tulppala, M, et al. Screening for coeliac disease in women with a history of recurrent miscarriage or infertility. Br J Obstet Gynaecol 1999; 106:171.
Farthing, MJ, Rees, LH, Edwards, CR, Dawson, AM. Male gonadal function in coeliac disease: 2. Sex hormones. Gut 1983; 24:127.
Frustaci, A, Cuoco, L, Chimenti, C, et al. Celiac disease associated with autoimmune myocarditis. Circulation 2002; 105:2611.

References 4 of 4
Curione, M, Barbato, M, De Biase, L, et al. Prevalence of coeliac disease in idiopathic dilated cardiomyopathy. Lancet 1999; 354:222.
Pastore, L, Lo Muzio, L, Serpico, R. Atrophic glossitis leading to the diagnosis of celiac disease. N Engl J Med 2007; 356:2547.
Lahteenoja, H, Toivanen, A, Viander, M, et al. Oral mucosal changes in coeliac patients on a gluten-free diet. Eur J Oral Sci 1998; 106:899.
Ludvigsson, JF, Montgomery, SM, Ekbom, A. Risk of pancreatitis in 14,000 individuals with celiac disease. Clin Gastroenterol Hepatol 2007; 5:1347.
Shaker, JL, Brickner, RC, Findling, JW, et al. Hypocalcemia and skeletal disease as presenting features of celiac disease. Arch Intern Med 1997; 157:1013.
Mustalahti, K, Collin, P, Sievanen, H, et al. Osteopenia in patients with clinically silent coeliac disease warrants screening. Lancet 1999; 354:744.
Meyer, D, Stavropolous, S, Diamond, B, et al. Osteoporosis in a north american adult population with celiac disease. Am J Gastroenterol 2001; 96:112.
Selby, PL, Davies, M, Adams, JE, Mawer, EB. Bone loss in celiac disease is related to secondary hyperparathyroidism. J Bone Miner Res 1999; 14:652.
Cellier, C, Delabesse, E, Helmer, C, et al. Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma. French Coeliac Disease Study Group. Lancet 2000; 356:203.
Fry, L. Dermatitis herpetiformis. Baillieres Clin Gastroenterol 1995; 9:371.

Celiac Disease: Beyond Bowels, Blood, & Bones

by Patricia Raymond on Jan 20, 2012

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