CLINICAL PRACTICE

Primary care management of vitamin D deficiency and liver disease Amanda Chaney, MSN, ARNP, FNP-BC (Nurse Practitioner) Department of Transplant, Mayo Clinic, Jacksonville, Florida

Keywords 25-Hydroxyvitamin D; chronic liver disease; nurse practitioners; vitamin D; liver. Correspondence Amanda Chaney, MSN, ARNP, FNP-BC, Department of Transplant, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224. Tel: 904-956-3200; Fax: 904-953-6178; E-mail: [email protected] Received: 3 December 2013; accepted: 17 April 2014 doi: 10.1002/2327-6924.12217

Abstract Purpose: Vitamin D deficiency is one of the most common medical conditions. Up to 96% of patients with liver disease have this deficiency. The purpose of this manuscript is to educate primary care nurse practitioners (NPs) of vitamin D deficiency and its proper management in patients with liver disease. Data sources: Information was compiled by reviewing the scientific literature on cirrhosis, liver disease, and vitamin D deficiency (CINAHL, MEDLINE, PubMed search engines). Conclusions: While the usual supplement dose for vitamin D deficiency is 1000 international units (vitamin D3 ) daily, vitamin D2 supplementation at doses of 50,000 international units can be given for correction. Primary care NPs can assist patients with liver disease with optimal nutrition and vitamin supplementation. Implications for practice: Primary care NPs should be aware of vitamin D deficiency in patients with liver disease. Vitamin D supplementation may be required in high doses in those patients with a moderate to severe deficiency. Repeat 25hydroxyvitamin D levels should be checked after supplementation is completed and yearly thereafter.

Background and significance Vitamin D has been shown to be extremely important for good health. Many healthcare providers are noting vitamin D to be essential for prevention of many diseases. There has been recent evidence that optimal levels of vitamin D can reduce the risk of cardiovascular disease, autoimmune and infectious diseases, diabetes mellitus, and malignancy and, of course, is known to prevent fractures and development of osteoporosis (Courbebaisse, Souberbielle, & Thervet, 2010; Holick, 2011; Pramyothin & Holick, 2012). Other studies have found that adequate vitamin D levels are directly related to a reduced risk for developing muscle weakness and sustaining falls, and provide a healthy immune system (Bischoff-Ferrari et al., 2004; Dhesi et al., 2002; Lemire, 1995; Stein & Shane, 2011). Vitamin D has also been noted to reduce the risk of hypertension and insulin resistance (Stein & Shane, 2011). Although it is easily available through sunshine exposure and dietary supplementation, many people are not getting enough of this important vitamin. In fact, one of the most widespread medical conditions in the world is vitamin D deficiency (Holick, 2011).

Journal of the American Association of Nurse Practitioners 27 (2015) 415–419  C 2015 American Association of Nurse Practitioners

Cirrhosis, or end-stage liver disease, is a life-threatening disease where normal liver tissue is replaced by scar tissue, thus inhibiting the normal functions of the liver. The scar tissue, or fibrosis, can gradually develop to cirrhosis. It can be caused by a variety of disorders, including chronic alcohol consumption or infections, such as hepatitis B or C (Anand, Melcher, & Schleyer, 2012). Occurring in approximately 360 cases per year 100,000 people in the United States, it is the 11th leading cause of death, with 30,000 deaths per year. Once a patient has developed cirrhosis, it is only a matter of time before decompensation occurs. Patients at this point require a liver transplant for survival. Primary care nurse practitioners (NPs) are providing treatment for patients with cirrhosis more now than ever before. Patients with cirrhosis frequently have complications of liver disease, including malnutrition and vitamin deficiencies. Vitamin D deficiency is common in all age groups and among all comorbidities. There have been several studies in the literature that find vitamin D deficiency is extremely prevalent in patients with cirrhosis. Some studies have noted vitamin D deficiency in patients with chronic hepatitis C infection and the deficiency is

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directly related to the degree of fibrosis (Gutierrez, Parikh, & Branch, 2011; Kitson & Roberts, 2012; Ladero et al., 2013). There is also an association with vitamin D deficiency and poor response to hepatitis C treatment with interferon (Kitson & Roberts, 2012; Ladero et al., 2013). Deficiency of vitamin D has been linked to the incidence of acute cellular rejection in postliver transplant patients (Bitetto et al., 2010).

Sources of vitamin D and association between vitamin D and the liver Sunlight produces vitamin D3 in the skin. This process occurs by transforming 7-dehydrocholesterol into vitamin D3 by ultraviolet light (Holick, 2007; Nair, 2010). Other sources of vitamin D3 include dietary sources, such as oily fish, shiitake mushrooms, egg yolk, and fortified foods (milk, orange juice, yogurts, cheeses, breakfast cereals). Vitamin D2 is usually consumed as a prescription supplement (Holick, 2007; Pramyothin & Holick, 2012). All types of vitamin D (D2 and D3 ) are metabolized in the liver to 25-hydroxyvitamin D, or 25(OH)D. The 25(OH)D is then processed in the kidneys to 1,25-dihydroxyvitamin D, which is the active form of vitamin D. The kidneys produce this based on parathyroid hormone (PTH) levels, as well as calcium and phosphorus levels (Holick, 2007). Measuring 25(OH)D levels is thought to be the best way to determine a patient’s vitamin D status (Gutierrez et al., 2011; Pramyothin & Holick, 2012). 1,25Dihydroxyvitamin D levels are not recommended to be measured to determine vitamin D status, as this level is affected by PTH, fibroblast growth factor, calcium, and phosphorus levels, and is frequently normal or elevated in patients with vitamin D deficiency (Pramyothin & Holick, 2012). Risk factors for developing vitamin D deficiency include older age, dark skin pigmentation, winter season, female gender, low consumption of vitamin D by food intake or supplementation, malnutrition, poor absorption, little to no sunlight exposure, or use of sunscreen during sunlight exposure (Pilz et al., 2011). Other factors for patients with liver disease include malnutrition, decreased absorption of fat-soluble vitamins because of cholestasis, malabsorption, the liver’s inability to convert vitamin D because of cellular damage, and hypoalbuminemia (Gutierrez et al., 2011; Stein et al., 2009). Other influences of decreased levels of vitamin D in the patient with cirrhosis could be chronic inflammation and decreased production of vitamin D binding protein in the liver (Gutierrez et al., 2011). Dietary vitamin D is absorbed through the intestinal lumen, which requires bile acids. In patients with cholestatic liver disease, there are insufficient concentrations of bile acids, which can lead to malabsorption of fat soluble vitamins, including vitamin D (Lindor, 1993). 416

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One careful consideration important to discuss is sun exposure. Sun exposure, although an excellent way to replete vitamin D levels, can be recommended only in minimal amounts because of the risk for skin damage and skin cancers from repeated exposure. This is a risk that one must take into serious consideration for those patients posttransplant given the amount of immunosuppression medications these patients are on to prevent rejection of the transplanted organ (Pramyothin & Holick, 2012). Ideally, patients are using sunscreen, thus minimizing their exposure to harmful UV sunlight. Unfortunately, while UV protection, it also inhibits production of vitamin D by the skin.

Definition of vitamin D deficiency When determining vitamin D deficiency, the provider must measure the patient’s serum 25(OH)D level. Vitamin D levels can be further characterized into degrees of insufficiency, moderate or severe. Levels of a serum 25(OH)D level of 21–29 ng/mL has been defined as subclinical vitamin D deficiency or vitamin D insufficiency (Holick, 2007; Pramyothin & Holick, 2012). Deficiency, according to the U.S. Endocrine Society, is 25(OH)D less than 20 ng/mL (Pramyothin & Holick, 2012). Another source differentiates the classifications as vitamin D sufficiency as greater than 75 ng/mL, vitamin D insufficiency as 50–75 ng/mL, and vitamin D deficiency as less than 50 ng/mL. It has been stated that the optimal range for best outcomes of several diseases is in between 75 and 100 ng/mL (Pilz et al., 2011). Crawford, Labio, Strasser, and McCaughan (2006) define vitamin D deficiency as a serum level of 25(OH)D lower than 40 nmol/L or 16 ng/mL (Crawford et al., 2006). It has been recommended that in order to have all the vitamin D health benefits, serum vitamin D levels should be greater than 30 ng/mL (Holick, 2007). Severe vitamin D deficiency has been stated to be levels less than 25 nmol/L or 10 ng/mL (Stein et al., 2009).

Cirrhosis and vitamin D deficiency As stated above, there have been several studies that have established that vitamin D deficiency in patients with cirrhosis is common. It has been approximated that up to 96% of patients waiting for liver transplant have vitamin D deficiency, and more severe deficiency has been noted for those patients with more severe liver disease (Crawford et al., 2006). A cross-sectional analysis by Stein et al. (2009) documented the vitamin D status of cardiac and liver transplant patients at the time of their transplant. Of 69 heart and liver transplant recipients, 33% were recipients of a liver transplant. The majority of patients (91%) had levels below 75 nmol/L. They

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identified that liver transplant recipients had lower vitamin D levels than the heart transplant recipients. Thirty percent of patients who received a liver transplant had severe vitamin D deficiency, five of them had undetectable levels (Stein et al., 2009). Another, more recent study showed that 87% of a select group of patients with chronic hepatitis C had vitamin D deficiency (Ladero et al., 2013). There has been other research that has found a relationship between vitamin D deficiency and biliary diseases, such as primary sclerosing cholangitis or primary biliary cirrhosis (Trautwein et al., 2000). In a prospective cohort study by Reese et al., a strong relationship was identified between vitamin D deficiency, albumin levels, and Model for End-Stage Liver Disease (MELD) scores. Documentation of the MELD score is important in this patient population, as higher scores (those greater than 25) have a significantly higher morbidity and mortality. Other findings revealed that low serum 1,25(OH)D levels remained low in liver transplant patients, but serum 25(OH)D and vitamin D binding protein levels are improved postliver transplant (Reese et al., 2012). Research done by Gutierrez identified vitamin D deficiency in association with worsening liver disease (Gutierrez et al., 2011). There have been studies specifically finding a direct relationship with vitamin D deficiency in patients with chronic hepatitis C infection and the degree of fibrosis (Gutierrez et al., 2011; Kitson & Roberts, 2012; Ladero et al., 2013). There is also an association with vitamin D deficiency and poor response to hepatitis C treatment with interferon (Kitson & Roberts, 2012; Ladero et al., 2013). Incidence of acute cellular rejection in posttransplant patients has been linked to vitamin D deficiency (Bitetto et al., 2010). There have been two studies that have associated vitamin D supplementation in those patients with hepatitis C virus (HCV) and vitamin D deficiency with improvement in their rate of sustained virologic response (Abu-Mouch, Fireman, Jarchovsky, Zeina, & Assy, 2011; Bitetto et al., 2011). It has been recommended that for patients with hepatitis C, 25(OH)D levels should be checked to determine vitamin D status (Gutierrez et al., 2011).

Overview of treatment options for vitamin D deficiency in patients with cirrhosis (Table 1) There has not been much research focused on establishing the best treatment plan for correcting vitamin D deficiency in patients with cirrhosis. This is largely thought to be because of funding issues. As vitamin D is a relatively inexpensive medication, there is not much interest in developing a clinical trial by pharmaceutical companies (Gutierrez et al., 2011). Also, vitamin D is available over the counter, so ensuring that patients are complying with only taking medication as part of the trial could prove to

Vitamin D deficiency and liver disease

be challenging (Gutierrez et al., 2011). For patients with chronic liver disease, providers should aim to maintain 25(OH) vitamin D levels greater than 30 ng/mL (Nair, 2010). It was recommended by Stein and Stane (2011) to prescribe vitamin D supplementation for all patients with vitamin D levels less than 30 ng/mL (Stein & Shane, 2011). According to Gutierrez et al., the goal vitamin D level should be greater than 35 ng/mL (Gutierrez et al., 2011). The absorption of calcium is markedly decreased when severe vitamin D deficiency is present (Pramyothin & Holick, 2012). PTH is stimulated with vitamin D deficiency, which leads to the body maintaining a normal calcium level by removing calcium from the bone and excreting more phosphorus via urine, resulting in osteomalacia in adults (Pramyothin & Holick, 2012). In order to prevent hypocalcemia, vitamin D deficiency must be corrected before giving bisphosphonates for those patients who already have significant bone loss (osteoporosis; Ebeling, 2009). Obtaining bone mineral density testing in these patients is important to determine if bisphosphonates will be needed after vitamin D deficiency is corrected. There has been documentation that vitamin D2 (ergocalciferol) and D3 (cholecalciferol) are both effective in attaining adequate vitamin D levels. One treatment approach is to prescribe 50,000 international units (IU) of D2 weekly for 8 weeks to reach a 25(OH)D level of greater than 30 ng/mL and to maintain the patient on 50,000 IU of D2 twice a month (Holick, 2011; Pramyothin & Holick, 2012). It was one physician’s experience that management this way for 6 years was effective in correcting vitamin D deficiency to levels above 30 ng/mL with no toxicity noted (Holick, 2011). Vitamin D2 (ergocalciferol) is the only FDA-approved form of vitamin D available by prescription in the United States (Holick, 2011). Vitamin D3 (cholecalciferol) is available as an over the counter medication in several doses ranging from 400 IU to 50,000 IU (Holick, 2011). It should be noted that vitamin D2 has a shorter half-life than vitamin D3 . By prescribing vitamin D3 , it is then thought that normal levels will be attained more rapidly (Armas, Hollis, & Heaney, 2004; Trang et al., 1998). In healthy individuals, it has been discussed that for every 1 ng/mL below the goal vitamin D level, 100 IU/daily of vitamin D3 should be prescribed (Gutierrez et al., 2011). One article recommended that patients with HCV, for levels below 10 ng/mL, should receive vitamin D3 4000 IU/day, for levels 10–20 ng/mL, should receive vitamin D3 2000 IU/day, and for levels 20–30 ng/mL, should receive vitamin D3 1000 IU/day. Repeat levels were recommended to be drawn in 3 months’ time. Also, if dietary intake of calcium is less than 1 g/day, supplementation with calcium citrate is suggested (Gutierrez et al., 2011). According to one source, oral vitamin D replacement was effective in chronic liver disease. The study showed 417

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Table 1 Patients with chronic liver disease High-dose vitamin D supplements needed

Maintenance with calcium and vitamin D

Vitamin D levels 30, continue on maintenance and recheck levels yearly Recheck levels yearly

Follow-up 25(OH)D levels should be drawn after 12 weeks and if levels are suboptimal, supplementation should be again given with close follow-up. Achieving levels greater than 35 ng/mL is recommended. Once levels are normalized, calcium with vitamin D supplementation should be given for maintenance. NPs can assist these patients with optimal nutrition and vitamin supplementation to maintain good health while living with the chronic illness of cirrhosis.

Acknowledgments The author would like to acknowledge Andrew Keaveny, MD, and Shon Meek, MD, PhD, for their assistance and furthering my understanding of this topic.

References Abu-Mouch, S., Fireman, Z., Jarchovsky, J., Zeina, A. R., & Assy, N. (2011). Vitamin D supplementation improves sustained virologic response in chronic hepatitis C (genotype 1)-naive patients. World Journal of Gastroenterology, 17(47), 5184–5190. doi:10.3748/wjg.v17.i47.5184 Anand, B., Melcher, M., & Schleyer, A. (2012). Cirrhosis. Clinical Key 2012. Retrieved from https://www.clinicalkey.com/#!/ContentPlayerCtrl/ doPlayContent/21-s2.0-1014768/–“scope”:”all”,”query”:”cirrhosis”˝ Armas, L. A., Hollis, B. W., & Heaney, R. P. (2004). Vitamin D2 is much less effective than vitamin D3 in humans. Journal of Clinical Endocrinology and Metabolism, 89(11), 5387–5391. doi:10.1210/jc.2004-0360 Bischoff-Ferrari, H. A., Dawson-Hughes, B., Willett, W. C., Staehelin, H. B., Bazemore, M. G., Zee, R. Y., & Wong, J. B. (2004). Effect of vitamin D on falls: A meta-analysis. Journal of the American Medical Association, 291(16), 1999–2006. doi:10.1001/jama.291.16.1999 Bitetto, D., Fabris, C., Falleti, E., Fornasiere, E., Fumolo, E., Fontanini, E., . . . Toniutto, P. (2010). Vitamin D and the risk of acute allograft rejection following human liver transplantation. Liver International, 30(3), 417–444. doi:10.1111/j.1478-3231.2009.02154.x Bitetto, D., Fabris, C., Fornasiere, E., Pipan, C., Fumolo, E., Cussigh, A., . . . Toniutto, P. (2011). Vitamin D supplementation improves response to antiviral treatment for recurrent hepatitis C. Transplant International, 24(1), 43–50. doi:10.1111/j.1432-2277.2010.01141.x Courbebaisse, M., Souberbielle, J. C., & Thervet, E. (2010). Potential nonclassical effects of vitamin D in transplant recipients. Transplantation, 89(2), 131–137. doi:10.1097/TP.0b013e3181c6910f Crawford, B. A., Labio, E. D., Strasser, S. I., & McCaughan, G. W. (2006). Vitamin D replacement for cirrhosis-related bone disease. Nature Clinical Practice Gastroenterology & Hepatology, 3(12), 689–699. doi:10.1038/ ncpgasthep0637

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Demetriou, E. T., Travison, T. G., & Holick, M. F. (2012). Treatment with 50,000 IU vitamin D(2) every other week and effect on serum 25-hydroxyvitamin D(2), 25-hydroxyvitamin D(3), and total 25-hydroxyvitamin D in a clinical setting. Endocrine Practice, 18(3), 399–402. doi:10.4158/EP11268.OR Dhesi, J. K., Bearne, L. M., Moniz, C., Hurley, M. V., Jackson, S. H., Swift, C. G., & Allain, T. J. (2002). Neuromuscular and psychomotor function in elderly subjects who fall and the relationship with vitamin D status. Journal of Bone and Mineral Research, 17(5), 891–897. doi:10.1359/jbmr.2002.17.5. 891 Ebeling, P. R. (2009). Approach to the patient with transplantation-related bone loss. Journal of Clinical Endocrinology and Metabolism, 94(5), 1483–1490. doi:10.1210/jc.2009-0205 Gutierrez, J. A., Parikh, N., & Branch, A. D. (2011). Classical and emerging roles of vitamin D in hepatitis C virus infection. Seminars in Liver Disease, 31(4), 387–398. doi:10.1055/s-0031-1297927 Holick, M. F. (2007). Vitamin D deficiency. New England Journal of Medicine, 357(3), 266–281. doi:10.1056/NEJMra070553 Holick, M. F. (2011). Vitamin D: A d-lightful solution for health. Journal of Investigative Medicine, 59(6), 872–880. doi:10.231/JIM.0b013e318214ea2d Kitson, M. T., & Roberts, S. K. (2012). D-livering the message: The importance of vitamin D status in chronic liver disease. Journal of Hepatology, 57(4), 897–909. doi:10.1016/j.jhep.2012.04.033 Ladero, J. M., Torrejon, M. J., Sanchez-Pobre, P., Suarez, A., Cuenca, F., de la Orden, V., . . . Agundez, J. A. (2013). Vitamin D deficiency and vitamin D therapy in chronic hepatitis C. Annals of Hepatology, 12(2), 199–204. Lemire, J. M. (1995). Immunomodulatory actions of 1,25-dihydroxyvitamin D3. Journal of Steroid Biochemistry and Molecular Biology, 53(1–6), 599– 602. Lindor, K. D. (1993). Management of osteopenia of liver disease with special emphasis on primary biliary cirrhosis. Seminars in Liver Disease, 13(4), 367–373. doi:10.1055/s-2007-1007365

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Nair, S. (2010). Vitamin D deficiency and liver disease. Gastroenterology & Hepatology, 6(8), 491–493. Pilz, S., Tomaschitz, A., Marz, W., Drechsler, C., Ritz, E., Zittermann, A., . . . Dekker, J. M. (2011). Vitamin D, cardiovascular disease and mortality. Clinical Endocrinology, 75(5), 575–584. doi:10.1111/j.1365-2265. 2011.04147.x Pramyothin, P., & Holick, M. F. (2012). Vitamin D supplementation: Guidelines and evidence for subclinical deficiency. Current Opinion in Gastroenterology, 28(2), 139–150. doi:10.1097/MOG.0b013e32835004dc Reese, P. P., Bloom, R. D., Feldman, H. I., Huverserian, A., Thomasson, A., Shults, J., . . . Leonard, M. B. (2012). Changes in vitamin D binding protein and vitamin D concentrations associated with liver transplantation. Liver International, 32(2), 287–296. doi:10.1111/j.1478-3231.2011.02638.x Rode, A., Fourlanos, S., & Nicoll, A. (2010). Oral vitamin D replacement is effective in chronic liver disease. Gastroenterologie Clinique et Biologique, 34(11), 618–620. doi:10.1016/j.gcb.2010.07.009 Stein, E. M., Cohen, A., Freeby, M., Rogers, H., Kokolus, S., Scott, V., . . . Shane, E. (2009). Severe vitamin D deficiency among heart and liver transplant recipients. Clinical Transplantation, 23(6), 861–865. doi:10.1111/j.1399-0012.2009.00989.x Stein, E. M., & Shane, E. (2011). Vitamin D in organ transplantation. Osteoporosis International, 22(7), 2107–2118. doi:10.1007/s00198-010-1523-8 Trang, H. M., Cole, D. E., Rubin, L. A., Pierratos, A., Siu, S., & Vieth, R. (1998). Evidence that vitamin D3 increases serum 25-hydroxyvitamin D more efficiently than does vitamin D2. American Journal of Clinical Nutrition, 68(4), 854–858. Trautwein, C., Possienke, M., Schlitt, H. J., Boker, K. H., Horn, R., Raab, R., . . . Brabant, G. (2000). Bone density and metabolism in patients with viral hepatitis and cholestatic liver diseases before and after liver transplantation. American Journal of Gastroenterology, 95(9), 2343–2351. doi:10.1111/j.1572-0241.2000.02269.x

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Primary care management of vitamin D deficiency and liver disease.

Vitamin D deficiency is one of the most common medical conditions. Up to 96% of patients with liver disease have this deficiency. The purpose of this ...
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