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Gastroparesis and Pernicious Anemia - 3/14/2013

posted Mar 14, 2013, 10:16 AM by Rohit Das   [ updated Mar 17, 2013, 1:46 PM by Purnema Madahar ]

Ugh – been a while…sorry things have been a bit crazy on my end. Anyway, we had a very interesting case of an elderly male who presented with symptoms consistent with gastroparesis, which was confirmed with gastric scintigraphy. Upon further workup, upper endoscopy revealed severe atrophic gastritis of the body and antrum in association with high-titer anti-parietal cell antibodies and low-normal Vitamin B-12 levels. SO MUCH to talk about:

·         What is gastroparesis? What causes it? How is it diagnosed?

·         What is pernicious anemia, and how is it diagnosed? How does it relate to gastroparesis?

·         How is Vitamin B12 handled by the body, and how can we accurately assess B12 deficiency?

What is gastroparesis? What causes it? How is it diagnosed?

·         Literally meaning “paralysis” of the stomach, gastroparesis refers to nonobstructive causes of delayed gastric emptying. Gastric motility and functioning is extremely complicated, relying on input from the autonomic nervous system, some integrative circuitry within the enteric nervous system, and finally stimulation of gastric smooth muscle cells. Defects anywhere along these pathways can result in delayed gastric emptying, but for many causes of gastroparesis the pathophysiology is not clear (including the one I’m writing about today…).

·         Gastroparesis is mostly a disease of women, with an age-adjusted incidence of 9.8 per 100,000 person years (2.4 for men). Symptoms are variable and nonspecific, including nausea (92%), vomiting (85% - usually of “old” food digested previously, often hours ago), abdominal bloating (75%) and early satiety (60%). Abdominal pain can also be present (50-80%), but is usually not the predominant symptom, does not correlate well with the severity of delayed gastric emptying, and responds poorly to treatment aimed for accelerating gastric emptying. A nice sign is the “succussion splash,” which is done by placing one’s stethoscope on the stomach, rocking the patient to and fro via their hips, and listening for a “splashing” sound which represents moving retained gastric contents. This can however occur with gastric outlet obstruction, and also dependent on the severity of delayed gastric emptying. So, albeit a nonspecific sign, a positive succussion splash is still very significant for SOMETHING going wrong with gastric emptying…plus, its just fun to do!!

·         There are a myriad of causes of gastroparesis, outlined below:

o   Idiopathic, Diabetes Mellitus, and Postsurgical - I lumped these because they represent over 80-90% of cases. Respectively, idiopathic represents 40-50%, DM – 20-30%, and postsurgical (bariatric surgery, partial gastric resection/vagotomy, or Nissen fundoplication) around 15-20%.

o   More on the DM front – gastroparesis is seen more commonly in type I disease (40-50%), but also in type 2 disease (~30%). It occurs in the context of associated microvascular complications, particularly peripheral neuropathy and dysautonomia. Thought to be due to impaired neural control of gastric motility at the level of the vagus nerve, diabetic gastroparesis is quite problematic, as it impairs absorption of drugs and leads to unpredictable glycemic control (delayed emptying and digestion with insulin on board = hypoglycemia). Very interestingly, hyperglycemia itself leads to acute, reversible delayed gastric emptying, apparently from impaired antral contractility as well as via vagal efferent dysfunction.

o   Direct Gastric Disorders – this includes chronic intestinal pseudoobstruction, gastric ulcers, atrophic gastritis, celiac disease, GERD, achalasia…

o   Collagen Vascular Disease – mainly scleroderma, SLE and amyloidosis

o   Endocrine/Metabolic – besides DM, can also be seen in CKD, hyperparathyroidism, and hypothyroidism

o   Miscellaneous – things I couldn’t particularly classify…Parksinson’s Disease, Gastric infections (mainly viral, and H. pylori if associated with chronic gastritis) and a RIDICULOUS amount of medications (see Table 3 of the attached review).

·         The gold standard for diagnosis is gastric scintigraphy. The test is done by labeling a tasty egg sandwhich with radiolabelled Technetium. The reason that eggs are used for the colloid is because the label binds avidly and remains bound at very low pH. After the meal, the percentage of the radiolabel present in the stomach is measured at 0, 1, 2 and 4 hours. Important normal numbers to remember are <70% at 2 hours and <10% at 4 hours. If <10% at 4 hours is used as a cutoff, the sensitivity and specificity for diagnosis gastroparesis approaches 100% and 85% respectively.

What is pernicious anemia, and how is it diagnosed? How does it relate to gastroparesis?

·         Pernicious anemia (PA) was first described in 1849, with the actual term coined in 1860. It refers to Vitamin B12 deficiency as a result of autoimmune-related atrophic gastritis. It is probably the most common cause of B12 deficiency, especially in those >60 years old, with an incidence of 4% and 2% in women and men, respectively. Vitamin B12 deficiency is a result of either intrinsic factor (IF) antibody (which binds the B12-binding site for IF, thus preventing its absorption in the terminal ileum) or by straightforward destruction of parietal cells, leading to impaired synthesis of IF – often, these two mechanisms act in concert.

·         The central pathophysiologic mechanism is destruction of parietal cells via an autoimmune mechanism, leading to atrophic gastritis (pathologically defined as a loss of mucosal folds and thinning of mucosa) in the parietal-cell containing parts of the stomach – the body and fundus. The antigen driving the autoimmune reaction is the gastric H+/K+-ATPase, as signified by the frequent presence of anti-parietal cell antibodies. Importantly, these antibodies are not thought to be pathogenic, but rather representative of the autoimmune reaction directed against parietal cells. Histologically, this is represented as mononuclear infiltration (plasma cells, T-cells, B-cells) of the lamina propria à gastric mucosa, ultimately leading to absolute reduction of parietal cells and replacement by mucus-containing cells (i.e., intestinal metaplasia).

·         The diagnosis of PA is made by documenting B12 deficiency (which we’ll talk about) with appropriate laboratory studies.

o   Intrinsic Factor Antibodies – This is the most specific test for PA, approaching 100%. However, the sensitivity is only 50-70% for serum detection, but approaches 90% if combined with testing of IF-antibodies in gastric juice (not commonly done…).

o   Parietal Cell Antibodies – Though one of the most sensitive tests for pernicious anemia (90-95%), it is very nonspecific. It is found in 30% of first-degree relatives with PA and also found frequently in patients with autoimmune endocrinopathies. For mainly those reasons, it can be used for screening, but certainly not for diagnostic confirmation.

o   Gastric biopsy (showing chronic gastritis of the fundus/body, sparing the antrum), high gastrin levels (due to stimulation of antral G-cells by achlorhydria) and low pepsinogen levels (due to accompanied destruction of gastric chief cells) are other tests that can also be useful when patients are anti-IF negative.

·         It’s not clear how, but studies have shown that chronic atrophic gastritis can cause significant delay in gastric emptying. In an older study from 1971, investigators looked at the gastric emptying of 16 patients with biopsy proven atrophic gastritis. Though they used a chromium radioactive label, the “meal half-life” of the case cohort (67.5 minutes) was significantly longer than the half-life of the control group (45.6 minutes).


How is Vitamin B12 handled by the body, and how can we accurately assess B12 deficiency?

·         We talked a lot about this in report, and certainly worth rehashing some key points. Though the terms Cobalamin (Cbl) and vitamin B12 are used interchangeably, there are actually several other Cbls in the body with similar nutritional properties – B12, or cyanocobalamin, is just one of many in its group of friends.

·         Cbl is mainly attained from meats, eggs and milk, and the amount in a typical Western diet (5-15 ug/d) is far more than what’s required by our body thankfully (2ug/day). Because of this, body stores are more than adequate, and it takes 2-5 years for Cbl deficiency to develop, even in the context of severe malabsorption from PA. To review, there are a few steps involved in absorption and transport of Cbl:

o   When food enters the stomach, Cbl is bound to proteins. Acid production in the stomach then does a couple of things – releases Cbl from proteins, and stimulates production of IF. In the setting of a low pH, Cbl binds to salivary haptocorrin (formally known as R-binder) and not IF.

o   In the neutral pH environment of the small intestine, IF displaces haptocorrin, binds Cbl, and the Cbl-IF complex is then absorbed by mucosal cells of the terminal ileum.

o   FINALLY, within enterocytes, Cbl is released from IF and bound to transport proteins. The most physiologically important transport protein is transcobalamin II (TC II), but only represents 10-30% of measurable serum B12 levels.

·         There are several tests to diagnose B12 deficiency – but I’ll focus on the two we most commonly use. The most straightforward one, serum Cbl measurement, has an extremely variable accuracy based on the study one reads. Our lab reports the lower end of normal as 210 pg/mL – BUT, in one study of elderly patients using Cbl metabolites (like MMA) as the “gold standard,” 50% of Cbl-deficient patients had levels <200 pg/mL, 36% were between 200-350 pg/mL, and 14% were >350pg/mL. My point – if you have levels that are classified as “normal” by our lab, you may actually be Cbl deficient; only at levels >400pg/mL can you confidently exclude Cbl deficiency.

·         A better, but more expensive, way to diagnose Cbl Deficiency is measurement of methymalonic acid (MMA). As depicted in Figure 1, the conversion of methylmalonic-CoA to succinyl Co-A is dependent on an enzyme that uses Cbl as a cofactor; with deficiency, there’s more methylmalonyl-CoA, and consequently more MMA (its precursor). In one study, 98% of patients with low Cbl levels, classic hematologic findings, and/or hematologic response to replacement have elevated MMA levels.

Attached are reviews on Gastroparesis as well as Pernicious Anemia. I recommend these as always, but especially worth reviewing the management principles for Gastroparesis, which I didn’t really delve into in this daily. Some key points I wanted to reinforce before I call it a day:

1)      Idiopathic gastroparesis is the most common etiology among the several potential causes. The best diagnostic test, easy, noninvasive and accurate, is gastric scintigraphy.

2)      Pernicious Anemia is the most common cause of Cbl Deficiency in the elderly, and diagnosed in the context of a positive anti-IF, or other supportive findings as above.

3)      Chronic atrophic gastritis can cause delay in gastric emptying via unclear mechanisms.

4)      A normal Cbl level DOES NOT effectively rule out Cbl deficiency, unless levels exceed 400 pg/mL. The best way to assess for it is measurement of methylmalonic acid (MMA). 


American Gastroenterological Association Technical Review on the Diagnosis and Treatment of Gastroparesis
AGA Clin Practice Committe; Gastroenterology 2004, Volume 127: 1592-1622

Epstein et. al., NEJM 1997, Volume 337 (20): 1441-48

Snow, Arch Int Med 1999, Volume 159: 1289-98
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