Common variants in the HLA-DQ region confer susceptibility to idiopathic achalasia

Idiopathic achalasia is characterized by a failure of the lower esophageal sphincter to relax due to a loss of neurons in the myenteric plexus(1,2). This ultimately leads to massive dilatation and an irreversibly impaired megaesophagus. We performed a genetic association study in 1,068 achalasia cases and 4,242 controls and fine-mapped a strong MHC association signal by imputing classical HLA haplotypes and amino acid polymorphisms. An eight-residue insertion at position 227-234 in the cytoplasmic tail of HLA-DQ beta 1 (encoded by HLA-DQB1*05:03 and HLA-DQB1*06:01) confers the strongest risk for achalasia (P = 1.73 x 10(-19)). In addition, two amino acid substitutions in the. extracellular …

Etiopathological aspects of achalasia: lessons learned with Hirschsprung's disease

SUMMARY The etiology of primary esophageal achalasia is largely unknown. There is increasing evidence that genetic alterations might play an important but underestimated role. Current knowledge of the genetic base of Hirschsprung's disease in contrast is far more detailed. The two enteric neuropathies have several clinical features in common. This association may also exist on a cellular and molecular level. The aim of this review is to enlighten those etiopathogenetic concepts of Hirschsprung's disease that seem to be useful in uncovering the pathological processes causing achalasia. Three aspects are looked at: (i) the genetic base of Hirschsprung's disease, particularly its major suscept…

Achalasia—an unnecessary long way to diagnosis

Although achalasia presents with typical symptoms such as dysphagia, regurgitation, weight loss, and atypical chest pain, the time until first diagnosis often takes years and is frustrating for patients and nevertheless associated with high costs for the healthcare system. A total of 563 patients were interviewed with confirmed diagnosis of achalasia regarding their symptoms leading to diagnosis along with past clinical examinations and treatments. Included were patients who had undergone their medical investigations in Germany. Overall, 527 study subjects were included (male 46%, female 54%, mean age at time of interview 51 ± 14.8 years). Dysphagia was present in 86.7%, regurgitation in 82…

Increased liver carcinogenesis and enrichment of stem cell properties in livers of Dickkopf 2 (Dkk2) deleted mice.

// Thorsten Maass 1 , Jens Marquardt 2 , Ju-Seog Lee 3 , Markus Krupp 4 , Peter Scholz-Kreisel 2 , Carolin Mogler 5 , Peter Schirmacher 5 , Martina Muller 1 , Heiner Westphal 6 , Peter R. Galle 2 , Andreas Teufel 1 1 Department of Internal Medicine I, University of Regensburg, Regensburg, Germany 2 I. Department of Medicine, University Medical Center Mainz, Mainz, Germany 3 Cancer Biology Program, MD Anderson Cancer Center, Houston, TX, USA 4 Department of Informatics, Johannes Gutenberg University Mainz, Mainz, Germany 5 Institute of Pathology, University of Heidelberg, Heidelberg, Germany 6 Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Develop…

Outcomes of pneumatic dilation in achalasia: Extended follow-up of more than 25 years with a focus on manometric subtypes

Background and aim Pneumatic dilation (PD) is the most popular nonsurgical treatment for achalasia. This study investigated predicting factors, including manometric subtypes for symptom recurrence in the long term, in patients with achalasia treated with a single PD. Methods Between 1983 and 2013, a total of 107 patients were treated initially with a single PD and included in this longitudinal cohort study. Outcomes were correlated with demographics, symptoms (Eckardt score), and esophagographic and manometric features. Manometric tracings were retrospectively classified according to the three subtypes of the Chicago classification. Results Ninety-one (85%) patients were successfully treate…

Atypische Präsentationen der Achalasie - Wie kommt es so oft zu Fehldiagnosen und Fallstricken?

Achalasia

Introduction Many physicians are inadequately familiar with the clinical features of achalasia. Often, it is not diagnosed until years after the symptoms arise. This is unfortunate, because a delay in diagnosis worsens the prognosis.

Murine genetic deficiency of neuronal nitric oxide synthase (nNOS-/-) and interstitial cells of Cajal (W/Wv): Implications for achalasia?

Background and aim Nitric oxide (NO) is an important inhibitory mediator of esophageal function, and its lack leads to typical features of achalasia. In contrast, the role of intramuscular interstitial cells of Cajal (ICC-IM) and vasoactive intestinal peptide (VIP) in lower esophageal sphincter (LES) function is still controversial. Therefore, we examined the function and morphology of the LES in vivo in NO-deficient (nNOS(-/-) ), ICC-IM-deficient (W/W(v) )-, and wild-type (WT) mice. Methods Esophageal manometry was performed with a micro-sized transducer catheter to quantify LES pressure, swallow evoked LES relaxation, and esophageal body motility. The LES morphology was examined by semiqu…

The HLA-DQβ1 insertion is a strong achalasia risk factor and displays a geospatial north-south gradient among Europeans.

Idiopathic achalasia is a severe motility disorder of the esophagus and is characterized by a failure of the lower esophageal sphincter to relax due to a loss of neurons in the myenteric plexus. Most recently, we identified an eight-amino-acid insertion in the cytoplasmic tail of HLA-DQβ1 as strong achalasia risk factor in a sample set from Central Europe, Italy and Spain. Here, we tested whether the HLA-DQβ1 insertion also confers achalasia risk in the Polish and Swedish population. We could replicate the initial findings and the insertion shows strong achalasia association in both samples (Poland P=1.84 × 10(-04), Sweden P=7.44 × 10(-05)). Combining all five European data sets - Central E…