Chronic calcium pyrophosphate crystal inflammatory arthritis induced by extreme hypomagnesemia in short bowel syndrome

Symptoms of short bowel syndrome (SBS) with mild, moderate or severe intestinal failure and/ or associated metabolic complications are estimated to occur if less than 200 cm of small bowel have been retained [1‐3]. It has been reported to show a wide spectrum of potential complications like underweight, food intolerance, osteoporosis, steatorrhea, chologenic diarrhea with loss of bile salts, electrolytes and vitamins as well as megaloblastic anemia or renal calcium oxalate stone formation etc. [1‐3]. Although SBS patients are often primarily referred to gastroenterological or nutritional hospitals, several other medical disciplines may be involved because of extraintestinal affections or complications like hormonal dysbalances, neurological symptoms (polyneuropathy), psychiatric or psychosocial co-morbidities (anxiety, chronic fatigue and depression) or orthopedic complications (osteoporosis) etc. Thus, often only an interdisciplinary approach may be helpful to manage patients with SBS, and at least, each patient has to be treated individually, based on more or less conserved intestinal functions or manifested deficiencies [1‐3]. The present case demonstrates how difficult clinical challenges can be in SBS and shows how intestinal resection may lead to severe metabolic consequences, recurrent joint attacks and food intolerances.

Patients may develop a plethora of clinical symptoms in SBS, when their remaining length of functional gut is insufficient for adequate absorption. Therefore, a supplementation of nutrients, water and electrolytes is usually required to maintain health and growth, respectively [10]. This case report describes a patient with extreme hypomagnesaemia and consecutive chronic CPPD crystal inflammatory arthritis due to a long history of SBS, which was inadequately supplemented and treated over years. Despite arthroscopy six years before CPPD deposition remained unrecognized. In the end, multiple current diagnostic procedures, including magnesium resorption test, revealed hypomagnesaemia as the most likely explanation for CPPD deposition. Other associated disorders such as hyperparathyreoidism, renal Mg loss and hemochromatosis were ruled out.

Since Mg-absorption testing demonstrated no resorption of Mg due to shortened small intestinal length with increased peristalsis because of lactose, fat and NSAID intolerance, the malabsorptive state and the SBS were considered as the reason for this extreme Mg deficiency. Hypomagnesaemia is a common feature of SBS. Fatty acids derived from either bacterial fermentation of malabsorbed carbohydrates or high dietary fat intake (long-chain triglycerides) bind Mg and prevent absorption [10]. Another contributing factor for Mg deficiency in SBS is hyperaldosteronism induced by loss of water and salt which increases renal wasting of Mg [11]. In addition, oral supplementation of Mg is known to cause intestinal motility and diarrhea, which can further compromise adequate Mg absorption. Finally, our patient had reduced 1,25-hydroxy-vitamin D levels, which further hampers normal jejunal Mg absorption. Thus, our patient had several pathophysiologic mechanisms contributing to hypomagnesaemia (See Figure 3 for illustration). Therefore, parenteral substitution of Mg along with other nutrients was required to assure a sufficient Mg supply [10].

Mg is a divalent cation mostly located intracellularly. It plays an important role in enzymatic processes. In healthy individuals homeostasis of Mg is regulated effectively, as sufficient mechanisms in the gastrointestinal tract and the kidney exist. However, if these mechanisms are affected in underlying disease, Mg depletion can cause a wide range of symptoms such as neuromuscular manifestations (muscular cramps, vertigo, tetany), cardiac and vascular manifestations (arrhythmias, hypertension), metabolic sequels and psychiatric manifestations (depression, fatigue) [11, 12].

As seen in this case, severe Mg depletion resulted in CPPD deposition with clinical manifestations of chronic inflammatory arthritis [13‐16] and was responsible for muscular weakness, fatigue and the depressive episode.

Chondrocalcinosis, is defined as the deposition of calcium pyrophosphate dihydrate in hyaline or fibrous cartilage [14]. In radiography delicate linear calcification of the cartilage can be seen. The prevalence of chondrocalcinosis increases with age (10-15% for people between 65 and 75 years) and is hence called sporadic in patients older than 60 years, whereas in younger individuals there are several putative underlying disorders causing CPPD deposition disease, such as hemochromatosis, hyperparathyroidism, hypomagnesemia or hypophosphatemia [14]. Although often asymptomatic, CPPD crystals can cause inflammation of joints resulting in attacks of pseudogout [17]. Typical joints affected by CPPD-induced arthritis are knees and ankles as demonstrated in our patient [14]. The association between low levels of Mg and CPPD deposition is not fully understood. As Mg acts as a cofactor for various phosphatases, a deficiency can lead to higher amounts of pyrophosphate, a necessary precursor for the formation of CPPD crystals [18].

The linkage between SBS and Mg depletion on the one hand, as well as between Mg depletion and CPPD deposition disease on the other hand, is known. Whereas Mg deficiency causing CPPD deposition is due to renal failure in most cases, such as in Bartter's or Gitelmann's syndrome [13, 18, 19], the connection of SBS causing extreme hypomagnesemia with subsequent CPPD deposition is scarce. To our knowledge, there have been only three cases described with a definite diagnosis of CPPD-induced arthritis (chondrocalcinosis) due to SBS [20].

Despite the rarity of this condition, it is important to know that SBS can be connected to CPPD deposition disease (chondrocalcinosis), presenting with acute or chronic arthritis and therefore SBS patients should be thoroughly investigated and, if necessary, receive parenteral treatment for Mg deficiency. Colchicine presents a favorable long-term medication with steroid-sparing effect, especially in the initial period of treatment [9]. Combined with several other therapeutic steps, intestinal Mg resorption rate was also improved by treating associated food intolerances, administering opioids to reduce bowel transit time and correcting vitamin D deficiency.