Non-hemic autoimmunity in CLL

One of the things I have been complaining about is the idea that there is a high degree of autoimmunity in CLL patients. It is absolutely true that autoimmune hemolytic anemia and ITP are more common in CLL and there may perhaps be a higher incidence of a few non-hemic autoimmunities like paraneoplastic pemphigus and nephrotic syndrome among CLL patients, but most autoimmune diseases are not commoner.

This is an interesting case report in which a patient with CLL developed severe celiac disease. The story of the celiac disease is particularly well told.

A 70-year-old gentleman chronic lymphocytic leukemia presented with a four-day history of weakness and profuse, watery diarrhea. He reported 7-8 bowel movements per day, all of which were large volume, watery and greenish-brown in color. The diarrhea was usually associated with crampy abdominal pain and bloating, which was partially relieved with defecation. He also noted occasional red-tinged toilet paper, although he denied any visible blood in the stool or melenotic stools. He complained of occasional "chills" although he denied any fevers or any nausea and vomiting. He reported a 20-30 lb. weight loss over the past month and complained of overwhelming fatigue, weakness and decreased work tolerance during the week prior to admission.

He was admitted for similar symptoms approximately four weeks prior to this admission. At that time a flexible sigmoidoscopy was essentially negative, and an EGD showed gastric and duodenal inflammation, but the ensuing gastric biopsy was negative. During that admission, the patient received treatment of his CLL with cytoxan and was placed on a lactose free diet. The diarrhea decreased to 1-2 bowel movements per day following these interventions and the patient was discharged home on a lactose free diet.

He was readmitted approximately one week prior to this admission, when he developed a new right foot drop. A diagnosis of idiopathic peripheral neuropathy was made with an MRI showing long-standing spinal stenosis. His diarrhea was present but not severe during this hospitalization. His lower extremity weakness improved during the course of stay, and he was discharged home, still on a lactose free diet, in good condition. However, immediately after discharge the patient's diarrhea returned in a severe form, culminating in the most recent admission.

His past medical history was significant for the aforementioned CLL, diagnosed in 1993. His disease had been well controlled until 1997 when new lymphadenopathy and increasing lymphocyte counts prompted treatment with two courses of fludaribine, after which the patient developed esophageal dysmotility. More recently, the disease was again found to be progressing and treatment with cytoxan and prednisone was instituted. The patient also has a history of hypertension, osteoarthritis, hypercholesterolemia, spinal stenosis and he is known to have had a goiter The patient has had a laminectomy in 1990, a supraclavicular lymph node biopsy in 9/00 (consistent with CLL), port-a-cath placement in fall of 2000 and past bilateral cataract surgeries.

His mother had a history of "thyroid disease" and died at age 90. His father died at age 84 with gastric cancer. He had a sister who died at birth and a has brother with coronary artery disease and coronary artery bypass grafting. His son is alive and healthy.

He is a retired printer with no smoking or alcohol history. He is married. His medications on admission were Cardura and Epogen 20,000 units SQ qd.

On examination, the patient was a pleasant 70-year-old male, NAD, alert and oriented to time, person and place. He was somewhat pale and fatigued appearing. His vitals were within normal limits. HEENT exam was unremarkable, and his oral mucosa was moist. He had shoddy cervical adenopathy bilaterally. His lungs were clear to auscultation bilaterally with no significant chest findings. His cardiac exam was notable for a 1/6 SEM heard best at the base. He had a mildly distended abdomen with a palpable spleen 3-4 fingerbreadths below the left costal margin. The liver edge was palpable at the right costal margin. His extremities were intact without cyanosis, clubbing or edema. There were 2 palpable, non-tender freely movable axillary nodes noted, both 1.5 cm, one in each axilla. The neurological exam was significant only for slightly decreased strength (4/5) with plantar flexion of the right ankle.

Lab tests at the time of admission showed a WBC of 36.9 with 92% lymphocytes, 5% monocytes and 0% segmented neutrophils. The hemoglobin was 9.8 and platelets were 145. His sodium was 138, potassium was 3.7, chloride was 114, bicarbonate was 14 and creatinine was 1.3. The BUN and glucose were normal. CXR on admission showed areas of atelectasis. The patient was admitted with a diagnosis of diarrhea, dehydration and known CLL.

At the time of admission, GI felt the most likely causes for this patient's diarrhea were: 1. Infiltration of CLL into the small bowel wall; 2. opportunistic infections (either micro or cryptosporidium) or; 3. bacterial overgrowth syndrome. Stool gram stains returned showing normal flora and the C. Difficile toxin assay was negative. He was placed on a clear liquid diet, but still had significant diarrhea. Fluid losses were replaced with IV hydration.

A colonoscopy was initially interpreted as normal, but the pathology report the following day was showed lymphocytic colitis, not related to colonic infiltration by CLL. The patient was placed on prednisone for the colitis.

An abdominal CT showed decreased adenopathy as compared to previous films and no obvious infiltration of disease into the bowel. The colon was noted to be moderately distended. The patient underwent an EGD four days post admission where biopsies of stomach and duodenum were obtained. There was no gross pathology noted.

Based on the CT results, it was clear that the patient responded to his last treatment with cytoxan and prednisone. A second dose was given on day 5 post admission and the patient was also started on allopurinol to prevent tumor lysis symptoms. EGD biopsy results were still pending at this time. As the patient was having 7-8 BM's per day of increasing volume and increasing abdominal distention, he was started on metronidazole as the diarrhea had not responded to steroids

On hospital day 6 a regular diet was again resumed and Imodium was started. The patient also began to c/o some vomiting episodes, which were attributed to the metronidazole. Sandostatin 100 mcg was begun in an attempt to reduce the fecal output. The patient was also switched from Imodium to Lomotil at this time, as the diarrhea continued to be severe. A 24-hour stool collection was yielded approximately 10 liters of stool were made during this collection.

On hospital day nine the duodenal biopsy results returned consistent with celiac sprue. The patient was immediately placed on a gluten free diet and antiendomysial and antigliadin antibodies tests were drawn.

Unfortunately, the diarrhea only increased in volume and by day 10, the patient began to have rigors and fever spikes. His blood and urine were cultured but no antibiotics were begun at this time. An abdominal US revealed no significant pathology. TPN was begun as an apparent 50lb weight loss was recognized over the past 6 weeks.

During the admission the patient had been consistently acidotic, with low HCO3 readings but increased Cl causing a non-anion gap acidosis, almost undoubtedly from the chronic diarrhea. This was becoming more severe and correction with bicarbonate in the IV fluids and acetate in the TPN was required. The sandostatin dosage was increased to 100 mcg tid. On day 11, the blood cultures were positive for gram positive cocci and the patient was placed Ceftriaxone and vancomycin. TPN was halted because of concerns over TPN use in a bacteremic patient, but was renewed after a discussion with ID. Antiendomysial and antigliadin antibody test results returned and both IgA and IgG antigliadin were positive. Interestingly, antiendomysial IgA was found to be negative.

In the early evening of day 11, the patient was somewhat more dyspneic and an EKG was ordered. This showed new onset atrial fibrillation with occasional PAC's. As the patient looked acutely ill, was extremely weak and still having massive diarrhea, it was decided to transfer the patient to the MICU for aggressive fluid resuscitation and more continuous monitoring.

The patient continued on TPN in the MICU and was also started on Neupogen for a low WBC count presumably secondary to the cytoxan treatment. He was given nothing by mouth and by Day 13 stool output had begun to decrease. The bacteremia was found to be S. pneumoniae that was sensitive to vancomycin but intermediately resistant to ceftriaxone. The patient's diarrhea continued to improve over the next two days. His TPN was discontinued on day 15 and he was placed back on a gluten free diet. The vancomycin was discontinued and the patient remained on ceftriaxone. He had been afebrile since day 2 of antibiotics. At this time he was place on fluconazole for esophageal candidiasis with odynophagia. He continued to improve and was transferred back to the floor on day 17 and discharged home on day 21 with no diarrhea, a good appetite and increased energy and strength subjectively. He was to continue with a gluten free diet at home.

Discussion

Celiac disease, often called celiac sprue, is an acquired sensitivity to the protein gluten. Exposure to the gliadin moiety of gluten is responsible for the characteristic histopathologic changes and the resulting clinical picture. The classic pathologic changes consist of flattening of the intestinal mucosa, hyperplasia of intestinal crypts and complete absence of normal villi. Remaining absorptive cells are cuboidal rather than columnar and the brush border is greatly reduced. Furthermore, tight junction abnormalities are present, causing an enhanced permeability of the mucosal barrier.

Interestingly, the length of the celiac lesion (ie: the amount of small bowel effected) varies greatly from patient to patient, and has a direct correlation with the severity of clinical disease. Consequently, there is a large spectrum of disease presentations ranging from asymptomatic to life-threatening "celiac crisis." The intestinal lesion may also range from involvement of only the proximal duodenum to complete small bowel involvement. If the lesion does not involve the entire small bowel, the proximal intestine is the most severely effected and the lesion decreases in severity distally.

Appropriate treatment (gluten-free diet) results in a return of normal intestinal architecture. The cytologic appearance of the surface absorptive cells improves first, often within a few days. Cells again become columnar and well developed brush borders began to appear. Later, villi began to lengthen and the crypts revert back to their usual size. The length of time required for complete restoration of gut mucosa is variable, with some patients still having biopsy proven changes years after gluten withdrawal.

Gluten is found in certain cereal grains including wheat, barley, and rye. It is not found in rice or corn, and oat flour is usually safe for celiac patients, although this is somewhat controversial. The gliadin moiety, a complex mixture of glutamine and proline rich polypeptides, seems to be the factor causing the mucosal damage. How gliadin causes the typical celiac mucosal alterations is not precisely known, but it is clear that both genetic and environmental factors are involved. Celiac disease is found in 10% of first order relatives of known celiac patients. Furthermore, a 70% concordance rate is noted in HLA identical twins. Genetic markers for celiac sprue have recently been elucidated. Approximately 95% of affected individuals inherit the DQA1*0501 and DQB1*0201 alleles, mapping on the HLA region of chromosome 6. These code for the HLA-DQ molecule DQ2. No known structural abnormalities in these DQ alleles have been found in celiac patients, and the majority of individuals who have these HLA haplotypes remain healthy. It is likely that these individuals are genetically susceptible to celiac development, but an immunologic or environmental trigger may be necessary for development of disease.

Immune mechanisms clearly play a role in sprue pathogenesis. Antigliadin antibodies are usually found in celiac sprue patients, in both serum and intestinal luminal secretions. These antibodies may participate in cell-mediated cytotoxic destruction of absorptive cells, or cause immune complex formation, which bind complement and cause local destruction. T- cell activation may also play a role, as many cells in the lamina propria of untreated patients are activated. This activation may cause the release of TNF and interferon, resulting in inflammation and epithelial cell damage. Interestingly, mucosal damage in graft-versus-host disease resembles that in celiac sprue, further suggesting that T-cell activation may play a role.

The environmental trigger causing immunologic activation has yet to be determined, but human type 12 adenovirus has an amino acid segment with high sequence homology to alpha-gliadin. Molecular mimicry of the viral segment by gliadin peptides may be the underlying trigger. The gliadin sequences are presented by the specific HLA heterodimers to gliadin specific T-cells. T-cell activation causes cytokine release and B-cell activation. B-cells produce antibodies that may cause antibody dependent cell-mediated cytotoxicity or complement mediated cytotoxicity. The end result is mucosal damage.

Celiac disease is found in about 1 in 1000 people in Europe, South America and North Africa. It effects the sexes equally and the initial presentation may be in any age group, although it is more common in children. The United States was thought to have a much lower incidence, but recent studies show antiendomysial antibodies present in about 8 of 2000 people. If this can be considered a diagnostic test, then the prevalence of celiac in the US is similar to other populations.

The clinical presentation of celiac disease can vary tremendously from patient to patient. The patient in this case presented with the most severe form of this disease, the so-called "celiac crisis," where pan-malabsorption lead to a life threatening nutritional deficit and non-anion gap acidosis. Initial presentation of celiac crisis in adulthood is rare, with most patients being children under two years.

The most common presenting signs and symptoms include diarrhea, weight loss, fatigue, bloating and flatulence. This patient had all of these including diarrhea of approximately 10 liters per 24 hours. Diarrhea is caused by increased stool volume and osmotic load delivered to the colon (secondary to malabsorption). Water and electrolytes are secreted into the small intestine rather than absorbed and if the ileum is involved, absorption of bile salts is impaired. Weight loss in sprue is variable as some patients may compensate by increasing their appetite tremendously, however some, like our patient, actually develop anorexia, predisposing them to marked weight loss.

Celiac disease can manifest in extraintestinal disease as well. Anemia is a very common adult presentation of sprue. It is usually caused by impaired iron of folate absorption in the duodenum, but may be related to vitamin B12 deficiency if the terminal ileum is involved. Mucosal and GI bleeding may also contribute to anemia. This bleeding is the result of impaired coagulability secondary to poor vitamin K absorption. Hyposplenism and thrombocytosis occurs in 50% of adults; the etiology of this is unknown. Osteopenic bone disease is common, resulting from poor calcium and vitamin D absorption. Secondary hyperparathyroidism may result, further increasing the destruction of bone matrix. Interestingly, patients with severe disease may sometimes have neurologic symptomatology. Lesions of either the central or peripheral nervous system have been found, resulting in muscle weakness, paresthesias and ataxia. Our patient was known to have a recent episode of idiopathic peripheral neuropathy causing right foot drop. It is possible this finding was directly related to his as of yet undiagnosed celiac disease.

Diagnosis of celiac disease has clinical, pathologic and serologic components. Clinically, in any patient presenting with intractable diarrhea and weight loss a diagnosis of celiac disease must be considered. The patient should also experience full clinical remission after the removal of gluten from the diet. The typical pathologic findings of flattened villi, hypertrophic crypts and absence of the brush border, should also be biopsy proven. Serologic testing has also become helpful in making the diagnosis. IgA and IgG antiendomysial and antigliadin antibodies are usually present in patients with true celiac sprue. Antiendomysial IgA is the most sensitive and specific test but may be falsely negative (along with antigliadin IgA) when the patient has IgA deficiency, a common associated disorder of celiac disease. This patient was both IgG and IgA antigliadin +, but IgA antiendomysial negative. IgG antiendomysial testing was not ordered. The finding of a negative IgA antiendomysial antibody should not cast doubt on this patient’s diagnosis, as tissue biopsy is still the gold standard.

At first glance, the treatment of celiac disease seems simple, complete removal of gluten from the diet. In reality however, a diet free of gluten is exceedingly difficult to achieve and maintain, especially here in the US where gluten is ubiquitous. Wheat, barley and rye must be completely avoided and oats should be avoided initially as their consumption may or may not exacerbate sprue. Wheat is often hidden in processed foods. It is sometimes found in ice cream, salad dressing, canned vegetables and soups, coffee, ketchup, mustard and candy bars. Therefore a skilled nutritionist is often required to help patients achieve and maintain a completely gluten free diet. Patients generally tolerate rice, soybean, corn, millet, buckwheat, sorghum and tapioca. Furthermore, patients often require replacement therapy in addition to gluten removal. Anemic patients may need iron, folate or vitamin B12 replacement. Electrolyte imbalances must be aggressively treated. In this patient, replacement of bicarbonate was necessary as he developed a significant non-anion gap metabolic acidosis. Serum calcium levels must be strictly monitored and almost all celiac patients should receive both calcium and vitamin D supplementation in an effort to stave off osteopenic changes.

Complications of celiac disease generally fall into three categories, malignancy, stricture and ulceration, and refractory sprue. Malignancy accompanying celiac disease was found in 11-13% of patients. The most common of these was T-cell lymphomas, followed by squamous cell carcinomas of the esophagus and small intestinal adenocarcinomas, the latter showing a full 80 fold increase over the expected population incidence. This patient had a previous diagnosis of CLL, but I was unable to find any studies linking this (or any other leukemia) with celiac sprue. Ulceration and stricture is a rare complication of sprue, but well documented. These patients often present with abdominal pain, intestinal bleeding and obstruction. Peritonitis can develop if not treated early and aggressively with surgical intervention. Finally, some patients may develop celiac disease, which is unresponsive to gluten withdrawal. These patients usually respond to removal of gluten initially, but will later experience relapses even with strict gluten avoidance. Some of these patients will respond to corticosteroid or immunosuppressive medications, but usually not permanently. Refractory sprue can often lead to death even with aggressive fluid and electrolyte management.

Prognosis of celiac patients is generally quite favorable as long as the condition is recognized and appropriate therapy is instituted. Of course, untreated sprue can often lead to life-threatening malnutrition and electrolyte abnormalities. Moreover, patients who develop one of the complications mentioned above will certainly have a much poorer prognosis. In general, patients with gluten responsive sprue and no complications have an only slightly elevated mortality rate as compared with controls, and most die of causes unrelated to their celiac disease.

Before assays for antiendomysial and antigliadin antibodies became available, we had to rely on Type II anti-reticulin antibodies as an indication that celiac disease might be present. In 1986 I published a paper demonstrating that such antibodies were no commoner in CLL patients than in age-matched individuals. Like the authors of this case report I am convinced that the celiac disease and CLL in this patients are unrelated. This goes to point out that treating the CLL in the hope that the autoimmunity might remit is dangerous and futile.

Another trap to avoid falling into is to think that if small lymphocytes are found in strange places, such as the bowel wall, that they must be pathological. In CLL, small lymphocytes are found everywhere.