**5. Metabolic bone disease and complications related to joints in CD**

The relationship of bone derangement and CD has been recognized since a long time, and can occur with or without gastrointestinal symptoms (**Table 2**). Low mineral density, reduced bone mass and increased fragility leading to increased risk of fracture is commonly seen in CD. These bone alteration are the consequence of impaired calcium and vitamin D absorption and secondary hyperparathyroidism, resulting primarily from the loss of villous cells in the proximal intestine, where calcium is mostly absorbed accounting for 90% of overall calcium absorption [42]. Minor amount of calcium is absorbed from stomach and intestine, the colon accounts for <10% of calcium absorption. Calcium absorption from intestine,


#### **Table 2.**

*Factors contributing to bone alteration in celiac disease.*

reabsorption from the kidneys and excretion from bones is tightly controlled. Calcium balance is regulated through the calcitropic hormone, parathyroid hormone, 1,25(OH)2 D3, exert complex coordinated activities to maintain normal serum calcium levels [43]. When the extracellular calcium concentration decreases, there is rapid increase in parathyroid hormone release that promotes bone turnover and calcium bone loss. Hyperparathyroidism (**Figure 3**) is common in patients with newly diagnosed CD, 27% in adults and 12–54% in children [44, 45]. It is more common in refractory C, rather than in those who responded on gluten free diet [46]. Low BMD in adult CD patients is related to secondary hyperparathyroidism and osteomalacia due to calcium and vitamin D malabsorption [47]. Vitamin deficiency is present in both females and males accounting for 71 and 64% respectively. Dietary vitamin D is absorbed as a fat soluble vitamin in small intestine, and because of intestinal involvement in CD its absorption decreases thus leading to deficiency of particular vitamin [48]. The other factor of hypovitaminosis is intestinal mucosal lesion [49]. Steatorrhea may also impair the absorption of 25(OH)D undergoing enterohepatic circulation, especially in acute exacerbation of CD. In patients with CD, the regulation of 1,25(OH)2D3 is through genomic action involving the classical vitamin D receptor (VDR), although non genomic regulator is also involved in its absorption [50]. VDR is normally expressed in duodenal mucosa of patients with CD, notwithstanding mucosal damage and atrophy of villi [51]. Although there is no difference in frequency of VDR gene is seen in patients with CD and healthy subjects, therefore VDR gene is unrelated to low BMD [52]. The main factor is reduced calbindin and calcium binding protein due to damaged intestinal mucosa which leads to calcium loss and secondary hyperparathyroidism [53]. In atypical patients of CD, many presented with back pain, diffuse musculoskeletal pain and proximal muscle weakness, due to osteomalacia, osteopenia and osteoporosis. All these patients have low BMD.

**75**

**Figure 4.**

*Cross-section of bone tissue-osteoporosis.*

**Figure 3.**

*Hyperparathyroidism.*

*Complications of Celiac Disease*

*DOI: http://dx.doi.org/10.5772/intechopen.80465*

compared to general population [55].

Osteopenia is found in in almost all patients with CD, either treated or untreated. It is even more common in patients who remained unrecognized. The prevalence of osteopenia and osteoporosis in adult is around 14–35% [54]. Osteoporosis (**Figures 4** and **5**) is characterized by low bone mass, micro architectural disruption and skeletal fragility resulting in decreased bone strength and increase risk fracture. It is not only dependent on BMD, but also related to rate of bone formation and resorption, bone size and shape and micro architecture. It has no clinical manifestation until one developed pain due to fracture. The commonest site of involvement of osteoporosis is either lumbar spine or neck of femur or radius. The commonest site of involvement is also lumbar spine accounting almost 26% [48]. The risk is almost doubled as compared to general population. It is more common in peripheral skeleton and common in males with classical presentation than females. Loss of bone density is much increased in older patients with late diagnosis as compared to younger patients and usually not resolved completely with gluten free diet. There is increased fracture risk, almost doubled in CD patients as

Children with CD are at risk of reduced BMD, hyperparathyroidism, decreased

calcium especially in those with untreated CD [56]. They may or may not have

## *Complications of Celiac Disease DOI: http://dx.doi.org/10.5772/intechopen.80465*

*Celiac Disease - From the Bench to the Clinic*

**Factors Mechanism of action** Hypocalcaemia Vitamin D deficiency

Intestinal mucosal damage

Inadequate calcium intake

Decreased intake of vitamin D

Estrogens and androgens

Diagnosis in adult life Lapses from GFD Active disease Low BMI Lifestyle factors

Increase of renal calcium excretion Impairment of osteoblast function Alteration of osteoclast resorption cycle

Steatorrhea

Steatorrhea

Bowel inflammation hormones Chronic release of proinflammatory cytokines PTH

Corticosteroids Reduction of intestinal calcium absorption

Additional risk factors Autoimmune alternations

*Factors contributing to bone alteration in celiac disease.*

Hypovitaminosis D Alterations in vitamin D metabolism

Alterations in calcium-transport mechanism

Decreased level of vitamin D-binding proteins

Reduced consumption of dairy products

reabsorption from the kidneys and excretion from bones is tightly controlled. Calcium balance is regulated through the calcitropic hormone, parathyroid hormone, 1,25(OH)2 D3, exert complex coordinated activities to maintain normal serum calcium levels [43]. When the extracellular calcium concentration decreases, there is rapid increase in parathyroid hormone release that promotes bone turnover and calcium bone loss. Hyperparathyroidism (**Figure 3**) is common in patients with newly diagnosed CD, 27% in adults and 12–54% in children [44, 45]. It is more common in refractory C, rather than in those who responded on gluten free diet [46]. Low BMD in adult CD patients is related to secondary hyperparathyroidism and osteomalacia due to calcium and vitamin D malabsorption [47]. Vitamin deficiency is present in both females and males accounting for 71 and 64% respectively. Dietary vitamin D is absorbed as a fat soluble vitamin in small intestine, and because of intestinal involvement in CD its absorption decreases thus leading to deficiency of particular vitamin [48]. The other factor of hypovitaminosis is intestinal mucosal lesion [49]. Steatorrhea may also impair the absorption of 25(OH)D undergoing enterohepatic circulation, especially in acute exacerbation of CD. In patients with CD, the regulation of 1,25(OH)2D3 is through genomic action involving the classical vitamin D receptor (VDR), although non genomic regulator is also involved in its absorption [50]. VDR is normally expressed in duodenal mucosa of patients with CD, notwithstanding mucosal damage and atrophy of villi [51]. Although there is no difference in frequency of VDR gene is seen in patients with CD and healthy subjects, therefore VDR gene is unrelated to low BMD [52]. The main factor is reduced calbindin and calcium binding protein due to damaged intestinal mucosa which leads to calcium loss and secondary hyperparathyroidism [53]. In atypical patients of CD, many presented with back pain, diffuse musculoskeletal pain and proximal muscle weakness, due to osteomalacia, osteopenia and

**74**

**Table 2.**

osteoporosis. All these patients have low BMD.

Osteopenia is found in in almost all patients with CD, either treated or untreated. It is even more common in patients who remained unrecognized. The prevalence of osteopenia and osteoporosis in adult is around 14–35% [54]. Osteoporosis (**Figures 4** and **5**) is characterized by low bone mass, micro architectural disruption and skeletal fragility resulting in decreased bone strength and increase risk fracture. It is not only dependent on BMD, but also related to rate of bone formation and resorption, bone size and shape and micro architecture. It has no clinical manifestation until one developed pain due to fracture. The commonest site of involvement of osteoporosis is either lumbar spine or neck of femur or radius. The commonest site of involvement is also lumbar spine accounting almost 26% [48]. The risk is almost doubled as compared to general population. It is more common in peripheral skeleton and common in males with classical presentation than females. Loss of bone density is much increased in older patients with late diagnosis as compared to younger patients and usually not resolved completely with gluten free diet. There is increased fracture risk, almost doubled in CD patients as compared to general population [55].

Children with CD are at risk of reduced BMD, hyperparathyroidism, decreased calcium especially in those with untreated CD [56]. They may or may not have

**Figure 3.** *Hyperparathyroidism.*

**Figure 4.** *Cross-section of bone tissue-osteoporosis.*

associated gastrointestinal symptoms. There is also risk less-than optimal peak bone mass leading to growth retardation as well. Bone density increases until the end of puberty. If there is lack of achievement of proper peak mass, there is more chance of development of osteoporosis in adulthood [57]. The rate of bone metabolism is also altered in children with CD, which is another factor for osteopathy [58]. In children who are unable to catch up growth need to be evaluated for concomitant growth hormone deficiency, as growth hormone exert its effect on bone mineral density.

Patients with CD commonly have osteomalacia (**Figures 6** and **7**) as well and presenting as aches and pain with bone tenderness unlike to osteoporosis. These patients also presented with proximal myopathy and spontaneous fracture [59]. The exact prevalence of osteomalacia though is not clear in CD [60]. The major factor for development of osteomalacia is decreased absorption of calcium and vitamin D. Diet plays a major and important role in proper bone mineralization. A gluten free diet is low in nutrient, vitamins and minerals, including calcium [61].

**Figure 5.** *Radiology-osteoporosis.*

**77**

*Complications of Celiac Disease*

osteoporosis and osteopenia.

*Looser's zone-osteomalacia.*

**6. Malignancies associated with CD**

known [63].

**Figure 7.**

*DOI: http://dx.doi.org/10.5772/intechopen.80465*

Thus they consume less vitamin D and calcium, as compared to normal diet [62]. It further decreases due to lactose intolerance resulting from decreased lactate production by the damaged villi. This factor further decreases BMD, and aggravates

Osteoarthritis is the most common type of arthritis world over. It is inflammatory condition due to damage of cartilage involving any joint of the body. It is commonly presents in patients with CD, but the exact causal relationship is not

The most important complication of CD is development of cancer. The incidence of gastrointestinal and non-gastrointestinal both is common among CD patients. The commonest among the malignancies is the gastrointestinal lymphomas accounting for 18% of all cancers. The gastrointestinal tract is the predominant site of extranodal lymphoma involvement. Primary lymphomas are less common than secondary lymphomas. Primary lymphomas typically involve any section of gastrointestinal tract from oropharynx to rectum [64]. It can involve single or multiple sites. These are usually non-Hodgkin's lymphomas although Hodgkin's lymphoma has been reported as well. The commonest site of involvement of non-Hodgkin's lymphoma is stomach, present in 68–75%, followed by small bowel than ileocecal junction. Diffuse colonic involvement is present only in 1% [65]. Distribution of primary lymphomas varies among population; gastric lymphoma is more common in United States, while intestinal lymphoma is seen in Middle East and Mediterranean areas. GI Lymphomas are commonly seen in patients with helicobacter pylori infection, autoimmune disease, immunodeficiency and immunosuppressive states, inflammatory bowel disease and CD. Both the T and B cell are commonly seen in patients with CD. The exact etiology of development of these malignancies is under controversy, both the autoimmune and inflammatory factors contribute to the risk. The T cell variant enteropathy-associated T-cell lymphoma (EATL) (**Figure 8**) involving the small intestine mostly, is the commonest malignancy seen in celiac disease, although uncommonly seen [66, 67]. It is most commonly found in adult males with a median age of 60 years. EATL patients mostly presented with acute bleeding, perforation or obstruction, or it should always be suspected if there is clinical deterioration of CD, despite on a strict gluten free diet. It is highly suggested to screen a patient for CD, even if not diagnosed before, if

**Figure 6.** *Tri-radiate pelvis-osteomalacia.*

*Complications of Celiac Disease DOI: http://dx.doi.org/10.5772/intechopen.80465*

**Figure 7.** *Looser's zone-osteomalacia.*

*Celiac Disease - From the Bench to the Clinic*

associated gastrointestinal symptoms. There is also risk less-than optimal peak bone mass leading to growth retardation as well. Bone density increases until the end of puberty. If there is lack of achievement of proper peak mass, there is more chance of development of osteoporosis in adulthood [57]. The rate of bone metabolism is also altered in children with CD, which is another factor for osteopathy [58]. In children who are unable to catch up growth need to be evaluated for concomitant growth hormone deficiency, as growth hormone exert its effect on bone mineral density. Patients with CD commonly have osteomalacia (**Figures 6** and **7**) as well and presenting as aches and pain with bone tenderness unlike to osteoporosis. These patients also presented with proximal myopathy and spontaneous fracture [59]. The exact prevalence of osteomalacia though is not clear in CD [60]. The major factor for development of osteomalacia is decreased absorption of calcium and vitamin D. Diet plays a major and important role in proper bone mineralization. A gluten free diet is low in nutrient, vitamins and minerals, including calcium [61].

**76**

**Figure 6.**

*Tri-radiate pelvis-osteomalacia.*

**Figure 5.**

*Radiology-osteoporosis.*

Thus they consume less vitamin D and calcium, as compared to normal diet [62]. It further decreases due to lactose intolerance resulting from decreased lactate production by the damaged villi. This factor further decreases BMD, and aggravates osteoporosis and osteopenia.

Osteoarthritis is the most common type of arthritis world over. It is inflammatory condition due to damage of cartilage involving any joint of the body. It is commonly presents in patients with CD, but the exact causal relationship is not known [63].
