Kfar Saba Syndrome:

Jacob Schor ND FABNO

May 11, 2008

I’ve seen three cases of ‘Kfar Saba Syndrome’ in as many weeks.  Don’t go rushing off to look this condition up in the Merck Manual, It’s not listed.  It’s my own name for the triad hypothyroidism, iron deficiency and B-12 deficiency when they present in the same patient.  It happens more often than you might guess.

Kfar Saba is a city northeast of Tel Aviv on the way to Nabulus.  The Hebrew means something like “grandfather’s village.”  This name has little to do with this condition.  Back in 2006, the American Journal of Medical Science published a paper written by several researchers from Kfar Saba.  Their paper got me started thinking these seemingly separate conditions were often linked. The name Kfar Saba stuck in my mind, and I’ve associated these new tidbits of knowledge with it.

The Kfar Saba paper was the first I’d read of the association between vitamin B-12 deficiency and autoimmune thyroid disease. Of the 115 people in the study, all of who had autoimmune thyroid disease (AITD), 32 of them had low vitamin B-12 levels. That's 28%; just less than 1 in 3. Of those patients who were B-12 deficient, 31% had pernicious anemia. [Ness-Abramof  2006]

This suggests a solid relationship between vitamin B-12 absorption and autoimmune thyroid disease.

Absorbing vitamin B-12 from food is a challenge. Many things can go wrong in the process. As vitamin B-12 is pulled out of food in the stomach, proteins secreted in the digestive tract, called salivary R-binders, attach to it. Acid from the stomach and pancreatic proteolytic enzymes are both needed to releases the B-12 from these ‘binders.' Without them, the B-12 will not be absorbed. [Marcoulis 1980]

Once free of the R-binders, B-12 is latched onto by a chemical called B-12 intrinsic factor. If this doesn’t happen B-12 will not be absorbed through the intestine into the blood. Specialized cells that line the stomach called parietal cells secrete intrinsic factor. The vitamin B12 and intrinsic factor complex can only be absorbed through a short section of the small intestine, called the terminal ileum. This is way down near the appendix. Even with adequate dietary B-12, moving it into the blood stream requires that the stomach generate both acid and intrinsic factor, a pancreas that generates the enzymes to release B-12 from the binding proteins, and small bowel capable of absorbing the B-12. Any of these can be a weak link leading to B-12 deficiency.

B-12 deficiency leads to a form of anemia called megaloblastic anemia in which red blood cells become swollen and bloated. On a complete blood count, the Mean Corpuscular Volume (MCV) increases and the Red Blood Cell (RBC) count decreases. The most common cause of B-12 deficiency is atrophic gastritis, a condition that damages the parietal cells preventing them from making intrinsic factor. We call this condition pernicious anemia. Sometimes the term pernicious anemia is used incorrectly to refer to any B-12 deficiency anemia, but technically, pernicious anemia is caused by atrophic gastritis.

Atrophic Gastritis is typically the result of an autoimmune process in which the immune system inappropriately makes antibodies that attack the parietal cells or intrinsic factor itself. Approximately 90% of individuals with pernicious anemia have antibodies for parietal cells, however only 50% of individuals with these antibodies have pernicious anemia.

 This Kfar Saba study was not the first to report an association between autoimmune thyroid disease and B-12 deficiency. An Italian study, published in the Archives of Internal medicine back in 1999 reported that 22 out of 62 autoimmune thyroid disease (AITD) patients had confirmed atrophic gastritis. Antiparietal cell antibodies were found in 68% (15/22) of patients with atrophic gastritis. Anemia was observed in 82% (18/ 22) of patients with AITD and atrophic gastritis. It was not just macrocytic, B-12 deficiency anemia, AITD patients also have a higher incidence of iron deficiency anemia.  [Centanni  1999]

Autoimmune gastritis causes atrophic gastritis that causes about one quarter of all cases of chronic iron deficiency anemia. Destruction of the parietal cells stops acid production in the stomach. A person needs acid in their stomach to absorb iron. Thus, atrophic gastritis can trigger both iron deficiency and B-12 deficiency. [Hershko  2007]

This complicates things. Iron deficiency causes microcytic anemia, a form of anemia where the red blood cells shrivel up in size. The Mean Corpuscular Volume (MCV) decreases. If B-12 and iron deficiencies coexist, the combined mean volume of big red blood cells caused by B-12 deficiency and small red blood cells caused by iron deficiency cancel each other out; the MCV may not look abnormal. The only hint on the CBC numbers may be an elevated RDW.  As I can never recall what exactly RDW abbreviates, let’s not elaborate further.

Of course, other conditions besides autoimmune attack can cause atrophic gastritis. The first that comes to mind is Helicobacter pylori. In fact, these infections may be a more common cause of atrophic gastritis than we initially thought.

Helicobacter pylori infections cause about one quarter of all cases of atrophic gastritis. [ Annibale  1997]   Treating and curing the H. pylori infection will usually improve the damaged tissue but not all the time. One study showed reduction in tissue damage in only about half of the patients cured of H. pylori infection. [Annibale 2000]

Here is where it starts to get complicated. There appear to be several diseases that seem closely related. Autoimmune thyroid disease is not a lone entity. One in four people who make antibodies that attack their thyroid, also make antibodies that attack the parietal glands and this can cause B-12 and iron deficiency.   It probably also lowers calcium absorption but let’s not complicate things further.

And then there is celiac disease. People with celiac disease have a higher than normal incidence of autoimmune thyroid disease, about twice the expected. It works both ways; people with thyroid disease are also more likely to have celiac disease. [Hadithi 2007]   Celiac disease also increases risk of B-12 deficiency. According to one study, 12% of celiac patients will be B-12 deficient. [Dickey 2002]

There are two possible explanations for this increase. First, celiac disease damages the terminal ileum where B-12 is absorbed. Second, celiac disease patients may make antibodies against parietal cells and so cause atrophic gastritis. Although about 10% of the B-12 deficient celiac patients have atrophic damage in the stomach and perhaps it is celiac triggered atrophic gastritis, the current opinion is this relationship is not autoimmune triggered. [Dickey 2002]

 A 2005 study looked at 190 patients with chronic unexplained iron deficiency anemia. Eight (5%) of the patients had celiac disease. Forty (27%) had autoimmune atrophic gastritis of whom 22 also had low serum vitamin B12 levels. Of the entire 190 patients, 29 (19%) only had H. pylori infection. But, H. pylori infection co-existed along with one of these other causes in 77 people (51%). None of the patients with celiac disease responded or improved with iron supplements. Most (71%) of the patients with autoimmune atrophic gastritis also failed to respond. About the same lack of response (68%) was seen with H. pylori infection. But of the patients who tested negative for these three conditions (AITD, H. Pylori and Celiac), almost all (89%) responded to iron supplements. Killing off the H. pylori improved the response to iron supplements. [Hershko  2005]

Studies tell us that there is no relationship between autoimmune thyroid disease and H. Pylori infection. [Tomasi  2005]

The primary symptoms of both iron deficiency and B-12 deficiency anemia and of autoimmune thyroid disease are the same. All three cause fatigue. Vitamin B-12 deficiency may also present with neurologic symptoms, typically peripheral glove and stocking numbness or neuropathy. Helicobacter pylori infection presents with upper gastrointestinal symptoms. Celiac disease is traditionally associated with digestive complaints, most commonly, chronic diarrhea. This has shifted and it is now believed that digestive complaints are not that common, occurring in less than 20% of patients. Osteopenia and osteoporosis are common in celiac patients. The explanation typically given is that this results from chronic malabsorption of calcium. It may also be a result of low vitamin B-12 levels that lead to increased homocysteine levels which are linked to osteoporosis.  Atrophic gastritis may present with the sort of complaints we associated with hypochlorhydria.  In fact hypothyroid patients often tell us they benefit from taking betaine hydrochloride don’t they?  This is a strong hint that atrophic gastritis is present.

 These recently reported associations add complexity to patients who present with hypothyroid disease, anemia, or even just fatigue.  Our tendency is to diagnose one of these conditions and figure we’ve done our job but, in fact, all three conditions coexist in patients far more often than we suspect.               

We need vigilance in all cases of autoimmune thyroid disease watching for symptoms of anemia. Atrophic gastritis, of either autoimmune or infectious origin, can cause both iron and B-12 deficiency and there is no reason that both deficiencies can't occur at the same time. If nearly a third of these patients will prove to be deficient, it seems reasonable to routinely test B-12 levels in this patient population along with iron and ferritin levels.

Patients on thyroid supplementation frequently still complain of fatigue.  It is easy to assume that they are taking insufficient thyroid hormone  and send them home with a larger dose but the fatigue could be due to either B-12 or iron deficiency or both.

These people are tired.  You will feel the urge to yawn the moment they walk into the room.  Don’t let their fatigue lull you into missing this.  Try to recall that weird name, Kfar Saba, which I use for this triad of conditions. Remember that in those tired people, hypothyroid, iron deficiency and B-12 deficiency can all be present.   Kfar Saba, Village of the Grandfathers,  think of tired grandfathers, very, very tired grandfathers. Maybe the name will stick.

References:

Annibale B et al. Atrophic body gastritis: distinct features associated with Helicobacter pylori infection. Helicobacter. 1997 Jun;2(2):57-64.

Annibale B et al. Cure of Helicobacter pylori infection in atrophic body gastritis patients does not improve mucosal atrophy but reduces hypergastrinemia and its related effects on body ECL-cell hyperplasia. Alimentary Pharmacology & Therapeutics. 14(5):625-634, May 2000.

Centanni M et al. Atrophic body gastritis in patients with autoimmune thyroid disease: an underdiagnosed association. Arch Intern Med. 1999 Aug 9-23;159(15):1726-30.

Dickey W. Low serum vitamin B12 is common in coeliac disease and is not due to autoimmune gastritis.Eur J Gastroenterol Hepatol. 2002 Apr;14(4):425-7.

Hadithi M et al. Coeliac disease in Dutch patients with Hashimoto's thyroiditis and vice versa. World J Gastroenterol. 2007 Mar 21;13(11):1715-22.

Hershko C et al. The anemia of achylia gastrica revisited. Blood Cells Mol Dis. 2007 Sep-Oct;39(2):178-83.

Hershko et al. Role of autoimmune gastritis, Helicobacter pylori and celiac disease in refractory or unexplained iron deficiency.  Haematologica. 2005 May;90(5):585-95.

Marcoullis G et al. Cobalamin malabsorption due to nondegradation of R proteins in the human intestine. Inhibited cobalamin absorption in exocrine pancreatic dysfunction.

 J Clin Invest. 1980 Sep;66(3):430-40.

Ness-Abramof R et al. Prevalence and evaluation of B12 deficiency in patients with autoimmune thyroid disease. Am J Med Sci. 2006 Sep;332(3):119-22.

Tomasi PA et al. Is there anything to the reported association between Helicobacter pylori infection and autoimmune thyroiditis? Dig Dis Sci. 2005 Feb;50(2):385-8.