Conditions Leading to Calcium and Vitamin D Deficiency

Vitamin D is a prohormone that can be synthesized in the skin or supplied in the diet (Figure 55-1). In the United States, many foods are vitamin fortified and contain vitamin D precursors. In patients with malabsorption, vitamin D precursors (ergocalciferol) are poorly absorbed. In liver disease, hydroxylation of vitamin D3 to 25-hydroxyvitamin D may be impaired. Following 25-hydroxylation of vitamin D in the liver, 1-hydroxylation occurs in the kidney through the action of 1a-hydroxylase. 1a-Hydroxylase expression is tightly controlled by parathyroid hormone (PTH) in response to serum calcium. The hormonally active 1,25-dihydroxyvitamin D activates calcium absorption in two general ways. First it increases expression of calbindin protein required for transport of calcium through villous ente-rocytes. 1,25-Dihydroxyvitamin D also increases paracellular calcium uptake through tight junctions. Calcium and vitamin D precursors in foods are absorbed largely in the duodenum and jejunum although data demonstrate that calcium is also absorbed in the colon (Hylander et al, 1990).

Low serum calcium activates a variety of homeostatic mechanisms to correct extracellular calcium concentrations. These include a rise in PTH (secondary hyperparathyroidism) and increased 1 a-hydroxylase activity in the kidney resulting in increased conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. Because of the underlying malabsorption and inability to increase calcium absorption from the gut, 1,25-dihydroxyvitamin D acts on bone to stimulate osteoclast differentiation and function and mobi lize skeletal calcium stores. Decreased absorption of vitamin D may result in osteomalacia (failure to mineralize new bone matrix). In conditions of malabsorption, both osteoporosis and osteomalacia may coexist. Bone biopsy is required to distinguish these entities but is generally not necessary for treatment.

Given this background, it is clear that GI diseases resulting in inflammation or pathology of the upper small bowel are particularly susceptible to osteoporosis. Examples of these include celiac sprue, Crohn's disease (CD), pancreatic insufficiency (PI) (Moran et al, 1997) and postgastrectomy (Vestergaard, 2003). CD patients are especially at risk if they have had extensive surgical resections or have diffuse intestinal disease. With improved medical and surgical therapy for CD, extensive surgical resections are thankfully the exception. Patients with jejuno-ileal bypass are also at risk for osteoporosis. It remains to be seen whether less drastic weight loss surgeries, such as gastric banding, will contribute to decreased BMD over time. In chronic cholesta-tic liver disease, vitamin D and calcium are malabsorbed and should be supplemented.

Because of the high risk for osteoporosis in these disorders, tests to evaluate BMD should make up part of the initial examination of the patient. Additional tests that are suggested are shown in Figure 55-1. An interpretation of bone tests is provided in Table 55-1. Improvement in the underlying malabsorption and calcium and vitamin D supplementation are required (Liedman et al, 1997). Hypocalcemia is a contraindication to the use of bisphosphonates (discussed below). Additional factors may contribute to low vitamin D and be indirectly related to GI or liver disease 7-Dehydrocholesterol

TABLE 55-2. Gastrointestinal and Hepatic Disorders Associated With Low Bone Mineral Density, Estimates of Osteopenia and Osteoporosis, and Estimates of Fracture Risk

Condition

Osteopenia

Osteoporosis

Fracture Risk

Inflammatory bowel diseases Crohn's disease

Ulcerative colitis Malabsorption

Celiac sprue

Postgastrectomy (multiple mechanisms, not all related to malabsorption)

Pancreatic insufficiency (cystic fibrosis) Liver disease Hepatic osteodystrophy

Pre-OLT/Post-OLT

40% increase over control population; 15 to 20% (silent fractures); risk may not be directly related to BMD No increase

40% (some studies have found little change within 5 years of surgery—long-term complication of surgery) 20% No data

80% increase over control population

> 60% in postmenopausal women with chronic liver disease, 5 to 15% in younger women and men 10 to 30%

Data presented reflect population-based studies when available. In general, the data are BMD = bone mineral density; OLT = orthotopic liver transplantation; PBC = primary biliary based on Z scores of the hip. For a comprehensive detailed review please see Bernstein et al, 2003; Leslie et al, 2003. cirrhosis.

in the skin is converted to 25-hydroxyvitamin D in response to sun exposure. Patients from northern climates with poor sun exposure or any patient that has been very ill and home or hospital bound may therefore become 25-hydroxyvitamin D deficient. Encouraging sun exposure is beneficial.

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