A genetic disease involving malabsorption of many nutrients, resulting from characteristic, if not specific, pathologic changes in the small intestinal mucosa induced by ingestion of the giiadin fraction of gluten. Giiadin is a mixture of high-molccular-weight cereal proteins found in wheat, rye, oats, and barley. In mosl patients, prompt clinical, biochemical, and histologic improvement follows the withdrawal ol’gliadin-containing cereal from the diet.
Celiac disease occurs throughout the world, but its prevalence is unknown. The incidence, which varies considerably in different parts of the world, is highest in western Ireland (1:300). Recent research indicates that the affected population is older than previously recorded; many cases are diagnosed during or after the seventh decade. This age-related skew—seen in the USA, Sweden, Scotland, and Ireland—probably reflects clinicians’ increased willingness to consider the diagnosis in the elderly.
Etiology and Pathogenesis
Celiac disease is closely associated with the human leukocyte antigens HLA-DQW2, HLA-DR3, and (to a lesser degree) HLA-B8.
Various mechanisms of etiology and palhogenesis have been proposed. One theory holds (hat the small inteslinal absorptive cell lacks one or more enzymes that normally break down giiadin peptides, and Ihe residual polypeptides injure the epithelial absorbing cells. Another theory suggests that susceptible patients absorb giiadin, which causes a humoral and a T-lymphocyle-dependent immune reaction, resulting in lysis and death of absorptive cells with a compensatory increase in crypt cell proliferation and a flat mucosal lesion. A third theory holds that glulen behaves like a lectin and binds (o pathologically altered carbohydrate structures of (he luminal small inteslinal cells.
Also, an amino acid sequence homology has been shown between a protein of the human adenovirus and a major α-gliadin component. This finding suggests that the immune response to antigenic determinants produced during a previous intestinal viral infection may be important in the pathogenesis of celiac disease. However, studies in animals and humans have failed 10 support this hypothesis and suggest that persistence of the adenovirus is not a major element in the pathogenesis of celiac disease. Thus, this disease probably has many causes, with genetic, immunologic, biochemical, and perhaps environmental factors all playing a role.
Symptoms and Signs
The clinical manifestations of celiac disease in the elderly arc subtle and variable. Most patients have steatorrhea, diarrhea, weight loss, and malnutrition, which may be mild. Certain nutritional deficiencies such as iron deficiency, osteomalacia with bone pain, or hypoprothrombin-emia; or fatigue with mild hematologic abnormalities such as unexplained macrocytosis, low folate reserve, a peripheral smear showing Howell-Jolly bodies (splenic atrophy), target cells, or thrombocytopenia may obscure the underlying disorder and prevent early diagnosis.
Physical findings vary among patients. Some appear chronically emaciated with pale mucous membranes and dry. scaly skin; in a small number, the dry, scaly skin is hyperpigmentcd. Blood pressure is normal or low. and peripheral edema often occurs. The hair may be thin, and the fingers may be clubbed. Usually, glossitis and cheilosis are present. The striking finding is abdominal distention wilh hyperactive bowel sounds. Other findings include positive Trousseau’s and Chvos-lek’s signs (associated wilh hypocalcemia), ecehymoses and hematomas resulting from decreased vitamin K absorption, skeletal deformities secondary to osteoporosis and osteomalacia, loss of height, evidence of peripheral neuropathy, and subacute combined degeneration.
Laboratory Findings
With fat malabsorption, microscopic examination of a stool specimen stained with Sudan III reveals increased tat droplets. A 24-h stool specimen usually weighs more than the normal 200 gm. Chemical fat determination of a 3- to 6-day stool specimen obtained while the patient ingests a 100-gtn fat diet shows fat excretion of IOlo40gm/24 h (normal is < 6 gm/24 h). A l4C-labclcd triolein breath test showing an increase in labeled breath carbon dioxide suggests fat malabsorption.
A 5-h urinary xylose excretion after ingesting 25 gm D-xylosc is 0.5 to 2.5 gm (normal is > 4.5 gm), and the blood level of xylose at 1 his < 30 mg/tlL (normal is > 30 mg/dL). Because of decreasei! renal function in the elderly, both urinary excretion and blood levels of xylose should be obtained. Hematologic findings include iron deficiency anemia with hy-pochromia and microcytosis on blood smear. Some patients have a megaloblastic anemia secondary to folic acid or vitamin Bi; deficiency or both. Serum folate levels range from 0.7 to 3.5 ng/mL (normal is > 3.5 ng/mL).
In patients with severe ileal damage. Ihe Schilling test reveals an excretion of < 8% of "Co-cyanocobalamin. This finding cannot be corrected by administering intrinsic factor or broad-spectrum antibiotics, thus differentiating celiac disease from pernicious anemia and blind-loop variants, respectively.
A useful screening test, serum carotene measurement invariably reveals levels < 50 μg/dL. Low levels of serum albumin, cholesterol. and vitamin A and a low prothrombin time (which can be corrected with IV vitamin K) may be found. In patients with osteomalacia, serum calcium is low, serum phosphorus is normal or low, and bone alkaline phosphatase is elevated. A bone biopsy revealing increased osteoid foci and widened osteoid seams confirms the diagnosis of osteomalacia. A generalized deficiency of intestinal disaccharidasc activity occurs secondary to brush border damage. Lactase is most affected. A lactose-hydrogen breath lest after lactose ingestion shows an increase in breath hydrogen > 20 ppm within 3 h.
Diagnosis
Diagnosis is based on characteristic histologic changes in a blind or endoscopic peroral jejunal mucosal biopsy. Those changes include a loss of villus architecture, markedly elongated intestinal crypts, cuboi-dal luminal epithelial cells with a loss of nuclear polarity, cytoplasmic basophilia, and vacuolization. The brush border is markedly attenuated. There is an apparent increase in intraepithelial cells. In the lamina propria, increased cellularity consists of immunoglobulin-producing plasma cells (IgM). lymphocytes, and some eosinophils and polymorphonuclear leukocytes.
Characteristically, the abnormal mucosa is confined to the proximal small intestine, but in severe cases, it extends to the entire small intestine. The lesions are not specific for celiac disease, but most patients who have them and who live in Ihe temperate zone have this disease and respond clinically, biochemically, and histologically to a gluten-free diet. Clinical or biochemical relapse or worsening of jejunal biopsy findings with a gluten or gliadin challenge confirms the diagnosis.
Measurement of circulating endomysial. reticulin, and gliadin antibodies is an important advance in Ihe serologic diagnosis of celiac disease. The IgA-class endomysial and reticulin antibodies are both sensitive and specific markers: the IgA-class gliadin antibodies are specific but less sensitive markers. All lliese markers may help in monitoring patient compliance with a gluten-free diet.
Treatment
The treatment of choice is a well-balanced diet containing normal amounts of fat, protein, and carbohydrate but no foods containing wheat, rye, barley, or oats. Lactose-free milk is recommended for patients with lactase deficiency. Symptoms and signs usually show improvement within days or weeks but may lake months.
Most patients who do not respond either are not adhering to the diet or have another disease such as giardiasis, lymphoma, Whipple’s disease, or collagenous sprue. (A rare disease, collagenous sprue is characterized by a severe lesion similar to the celiac disease lesion hut with broad bands of fibrosis and collagen beneath the basement membrane. The prognosis is generally poor.)
A few patients respond initially to gluten withdrawal but then relapse despite strict adherence lo the diet. Some of these refractory or unclassified celiac disease patients may respond lo treatment with high doses of corticosteroids (such as prednisone 60 mg/day for about I mo) or other immunosuppressive drugs, such as az.athioprine or cyclophosphamide. Others, despite such therapy, have a relentless course usually culminating in death.
Supplemental therapy: Patients with iron deficiency anemia should receive supplemental ferrous sulfate 325 mg tid, while those with folic acid deficiency should receive folic acid 5 mg/day for I mo, followed by a maintenance dosage of 1 mg/day. Patients with vitamin B12 deficiency should receive 100 μg vitamin B12 IM daily for 2 wk, then 100 μ-g monthly. About 1200 mg/day of elemental calcium corrects calcium deficiency (see TABLE 58-1); I to 4 gm/day of magnesium gluconate corrects magnesium deficiency.
Patients with radiologic evidence of osteopenic bone disease require I to 3 gm/day of elemental calcium plus 50,000 u./day of vitamin D. Vitamin K 10 mg IV should be given slowly (ie, 1 mg/min) to correct prolonged prothrombin time. Severe reactions, including fatalities, have occurred during or immediately after IV injection. Thus, IV vitamin K should be given only to quickly correct prothrombin time; then oral vitamin K (phytonadione 10 mg once a day) should be given. Therapeutic formula multivitamin preparations containing vilamin A, thiamine, riboflavin, niacin, pyridoxine, vitamin C, and vitamin E should be administered to patients with prolonged, severe malabsorption.
