Outcomes after pancreaticoduodenectomy with or without preoperative hyperbaric oxygen therapy.

Background: Hyperbaric oxygen (HBO2) therapy is an alternative method against the deleterious effects of ischemic/reperfusion (I/R) injury and its inflammatory response. This study assessed the effect of preoperative HBO2 on patients undergoing pancreaticoduodenectomy. Study Design: Patients were randomized via a computer-generated algorithm. Patients in the HBO2 cohort received two sessions of HBO2 the evening before and the morning of surgery. Measurements of inflammatory mediators and self-assessed pain scales were determined pre-and postoperatively. In addition, perioperative variables and long-term survival were collected and analyzed. Data are presented as median (mean ± SD). Results: 33 patients were included; 17 received preoperative HBO2, and 16 did not. There were no intraoperative or postoperative statistical differences between patients with or without preoperative HBO2. Erythrocyte sedimentation rate (ESR), IL-6, and IL-10 increased slightly before returning to normal, while TGF-alpha decreased before increasing. However, there were no differences with or without HBO2. At postoperative day 30, the pain level measured with VAS score (Visual Analog Score) was lower after HBO2 (1 ± 1.3 vs. 3 ± 3.0, p=0.05). Eleven (76%) patients in the HBO2 cohort and 12 (75%) patients in the non- HBO2 had malignant pathology. The percentage of positive lymph nodes in the HBO2 was 7% compared to 14% in the non-HBO2 (p<0.001). Overall survival was inferior after HBO2 compared to the non- HBO2 (p=0.03). Conclusions: Preoperative HBO2 did not affect perioperative outcomes or significantly change the inflammatory mediators for patients undergoing robotic pancreaticoduodenectomy. Long-term survival was inferior after preoperative HBO2. Further randomized controlled studies are required to assess the full impact of this treatment on patients' prognosis.

Perioperative Platelet Count Ratio Predicts Long-Term Survival after Left Pancreatectomy and Splenectomy for Pancreatic Adenocarcinoma.

BACKGROUND: The value of platelet characteristics as a prognostic factor in patients with pancreatic adenocarcinoma (PDAC) remains unclear. METHODS: We assessed the prognostic ability of post-splenectomy thrombocytosis in patients who underwent left pancreatectomy for PDAC. Perioperative platelet count ratio (PPR), defined as the ratio between the maximum platelet count during the first five days following surgery and the preoperative level, was assessed in relation to long-term outcomes in patients who underwent left pancreatectomy for PDAC between November 2008 and October 2022. RESULTS: A comparative cohort of 245 patients who underwent pancreaticoduodenectomy for PDAC was also evaluated. The median PPR among 106 patients who underwent left pancreatectomy was 1.4 (IQR1.1, 1.8). Forty-six had a PPR ≥ 1.5 (median 1.9, IQR1.7, 2.4) and 60 had a PPR < 1.5 (median 1.2, IQR1.0, 1.3). Patients with a PPR ≥ 1.5 had increased median overall survival (OS) compared to patients with a PPR < 1.5 (40 months vs. 20 months, p < 0.001). In multivariate analysis, PPR < 1.5 remained a strong predictor of worse OS (HR 2.24, p = 0.008). Among patients who underwent pancreaticoduodenectomy, the median PPR was 1.1 (IQR1.0, 1.3), which was significantly lower compared to patients who underwent left pancreatectomy (p > 0.001) and did not predict OS. CONCLUSION: PPR is a biomarker for OS after left pancreatectomy for PDAC. Further studies are warranted to consolidate these findings.

Current Operative Approaches to the Diseased Gallbladder. Diagnosis and Management Updates for General Surgeons.

Cholecystitis is a common diagnosis which requires management by general surgeons. Morbidity from cholecystitis is often life-threatening, especially in patients with underlying liver cirrhosis or other medical comorbidities. Diagnosis and management of this disease can vary among providers and hospitals. The decision to utilize a radiological or endoscopic temporizing maneuver in severe acute cholecystitis and the timing of later definitive cholecystectomy are relevant points of discussion within general surgery societies. In the last 5 years, the use of intraoperative ductal imaging by conventional vs fluorescence cholangiography had gained significant interest due to the widespread availability of indocyanine green. Finally, the operative strategies and how to manage intra-/postoperative complications are very important to optimizing patient outcomes. In this review paper, we discuss all treatment aspects of cholecystitis and provide updates in its management.

Watchful Waiting After Radiological Guided Drainage of Intra-abdominal Abscess in Patients With Crohn's Disease Might Be Associated With Increased Rates of Stoma Construction.

Background: Management of spontaneous intra-abdominal abscess (IAA) in patients with Crohn's disease (CD) with radiologically guided percutaneous drainage (PD) was debated. Methods: This is a secondary analysis from a multicenter, retrospective cohort study of all the patients with CD who underwent PD followed by surgery at 19 international tertiary centers. Results: Seventeen patients (4.8%) who did not undergo surgery after PD were compared to those who had PD followed by surgical intervention 335/352 (95.2%). Patients who had PD without surgery were those with longer disease duration, more frequently had previous surgery for CD (laparotomies/laparoscopies), enteric fistula, on steroid treatment before and continue to have it after PD. Patients who had PD without subsequent surgical resection had a higher risk of stoma construction at later stages 8/17 (47.1%) versus 90/326 (27.6%) (P < .01). Patients with PD with no subsequent surgery had numerically higher rates of abscess recurrence 5/17 (29.4%) compared to those who had PD followed by surgery 45/335 (13.4%) the difference was not statistically significant (P = .07). Conclusions: Even with the low number of patients enrolled in this study who had PD of IAA without subsequent surgery, the findings indicate a markedly worse prognosis in terms of recurrence, length of stay, readmission, and stoma construction. Watchful waiting after PD to treat patients with spontaneous IAA might be indicated in selected patients with poor health status or poor prognostic factors.

The Effect of Body Mass Index on Patients' Outcomes Following Robotic Distal Pancreatectomy and Splenectomy.

Background and Objectives: Obesity has increased over the past decade, yet the correlation among body mass index (BMI), surgical outcomes, and the robotic platform are not well established. This study was undertaken to measure the impact of elevated BMI on outcomes after robotic distal pancreatectomy and splenectomy. Methods: We prospectively followed patients who underwent robotic distal pancreatectomy and splenectomy. Regression analysis was utilized to identify significant relationships with BMI. For illustrative purposes, the data are presented as median (mean ± SD). Significance was determined at p ≤ 0.05. Results: A total of 122 patients underwent robotic distal pancreatectomy and splenectomy. Median age was 68 (64 ± 13.3), 52% were women, and BMI was 28 (29 ± 6.1) kg/m2. One patient was underweight (< 18.5 kg/m2), 31 had normal weight (18.5-24.9 kg/m2), 43 were overweight (25-29.9 kg/m2), and 47 were obese (≥ 30 kg/m2). BMI was inversely correlated with age (p = 0.05) but there was no correlation with sex (p = 0.72). There were no statistically significant relationships between BMI and operative duration (p = 0.36), estimated blood loss (p = 0.42), intraoperative complications (p = 0.64), and conversion to open approach (p = 0.74). Major morbidity (p = 0.47), clinically relevant postoperative pancreatic fistula (p = 0.45), length of stay (p = 0.71), lymph nodes harvested (p = 0.79), tumor size (p = 0.26), and 30-day mortality (p = 0.31) were related to BMI. Conclusion: BMI has no significant effect on patients undergoing robotic distal pancreatectomy and splenectomy. BMI greater than 30 kg/m2 should not defer proceeding with robotic distal pancreatectomy with splenectomy. Limited empirical evidence exists in the literature regarding patients with a BMI greater than 30 kg/m2, and thus any proposed operative intervention should invoke sufficient planning and preparation.

Does metabolic syndrome affect perioperative outcomes in patients undergoing robotic hepatectomy? A propensity score-matched analysis.

BACKGROUND: Metabolic syndrome is a known risk factor for postoperative complications after general surgical procedures. Literature analyzing perioperative outcomes of patients with metabolic syndrome undergoing a minimally invasive hepatectomy is limited. We sought to investigate if metabolic syndrome significantly impacts the perioperative course and outcomes of patients undergoing robotic hepatectomy. METHODS: With IRB, we prospectively followed patients who underwent robotic hepatectomy from 2016 through 2020. A 1:1 propensity score-matched (PSM) analysis was applied to patients with and without metabolic syndrome. Demographic and clinical data were analyzed for those cohorts before and after PSM. Metabolic syndrome was defined as BMI ≥ 28.8 kg/m2, diabetes, and hypertension. RESULTS: A total of 272 patients underwent robotic hepatectomy, 39 (14%) of whom had metabolic syndrome. After performing PSM, we ended up with 74 patients, 37 in each cohort, 28% of them had liver cirrhosis. Patients with metabolic syndrome had higher BMI (34 ± 5.6 vs. 28 ± 5.9 kg/m2, p < 0.001) and MELD scores (10 ± 4.5 vs. 8 ± 3.2, p < 0.001) compared to patients without metabolic syndrome. Additionally, patients with metabolic syndrome had an increased incidence of liver cirrhosis (33% vs. 9%, p = 0.0002). Following PSM, BMI (34 ± 5.7 vs. 26 ± 4.4 kg/m2, p < 0.001) was the only preoperative variables associated with metabolic syndrome. There were no statistical differences before and after PSM between patients with and without metabolic syndrome in terms of intraoperative metrics including operative time, blood loss, conversion to 'open,' and intraoperative complications. All postoperative outcomes metrics before and after PSM did not correlate with the presence or absence of metabolic syndrome. CONCLUSIONS: Metabolic syndrome had no impact on intra- or postoperative metrics, complications, or outcomes after robotic hepatectomy. We believe that the robotic approach may mitigate the adverse effects of metabolic syndrome for patients undergoing robotic hepatectomy.

Diagnosis and Contemporary Management of Necrotizing Pancreatitis.

BACKGROUND: Acute pancreatitis is a common diagnosis which requires a prompt diagnosis and management by a multidisciplinary team with often general surgeons as the initial provider. Morbidity and mortality from an acute pancreatitis can be very high, especially in patients with a progressive worsening acute pancreatitis developing into pancreatic necrosis in the setting of multiple underlying medical comorbidities. PURPOSE: In this review paper, we discuss all aspects of acute pancreatitis and its potential complications, as well providing updates in the modern management of necrotizing pancreatitis. Practicing general surgeons need to be aware of the evolution in the diagnosis and treatment of this disease. RESEARCH DESIGN: We conducted a review of literature of evidence and management options for acute pancreatitis, including all published manuscripts from 2012 to 2022. RESULTS: Diagnosis and management of this disease can vary among specialiaties. The decision to utilize a percutaneous or endoscopic techniques are relevant points of discussion within general surgery and gastroenterology societies. In the past decade, the use of advanced endoscopic interventions has slowly replaced conventional open surgery in managing complications of acute severe pancreatitis. CONCLUSION: Acute pancreatitis is a disease which requires multidisciplinary approach with evolving treatment options to less invasive nonsurgical methods.

A Single Institution's Experience With Robotic Minor and Major Hepatectomy.

BACKGROUND: Minimally invasive liver resection is gradually becoming the preferred technique to treat liver tumors due its salutary benefits when compared with traditional "open" method. While robotic technology improves surgeon dexterity to better perform complex operations, outcomes of robotic hepatectomy have not been adequately studied. We therefore describe our institutional experience with robotic minor and major hepatectomy. MATERIALS AND METHODS: We prospectively study all patients undergoing robotic hepatectomy from 2016 to 2020. RESULTS: A total of 220 patients underwent robotic hepatectomy. 138 (63%) were major hepatectomies while 82 (37%) were minor hepatectomies. Median age was 63 (62 ± 13) years, 118 (54%) were female. 168 patients had neoplastic disease and 52 patients had benign disease. Lesion size in patients who had undergone minor hepatectomy was 2 (3 ± 2.5) cm, compared to 5 (5 ± 3.0) cm in patients who undergone major hepatectomy (P < .001). 97% of patients underwent R0 resections while none of the patients had R2 resection. Operative duration was 226 (260 ± 122.7) vs 282 (299 ± 118.7) minutes (P ≤ .05); estimated blood loss was 100 (163 ± 259.2) vs 200 (251 ± 246.7) mL (P ≤ .05) for minor and major hepatectomy, respectively. One patient had intraoperative bleeding requiring "open" conversion. Nine (4%) patients had experienced notable postoperative complications and 2 (1%) patients died postoperatively. Length of stay was 3 (5 ± 4.6) vs 4 (5 ± 2.8) days for minor vs major hepatectomy (P = .84). Reoperation and readmission rate for minor vs major hepatectomy was 1% vs 3% (P = .65) and 9% vs 10% (P = .81), respectively. DISCUSSION: Robotic major hepatectomy is safe, feasible, and efficacious with excellent postoperative outcomes.

Inflammatory markers may predict post-operative complications and recurrence in Crohn's disease patients undergoing gastrointestinal surgery.

BACKGROUND: Most Crohn's Disease (CD) patients will require surgical intervention over their lifetime, with considerably high rates of post-operative complications. Risk stratification with reliable prognostic tools may facilitate clinical decision making in these patients. Blood cell interaction based inflammatory markers have proven useful in predicting patient outcomes in oncological and benign diseases. The aim of this study was to investigate their prognostic value in CD patients undergoing surgery. METHODS: A retrospective single institution study of CD patients who underwent surgery between the years 2008 and 2019 was conducted. Data were collected from medical records and analysed for association of Platelet-to-Lymphocyte Ratio (PLR), Neutrophil-to-Lymphocyte Ratio (NLR), Lymphocyte-to-Monocyte Ratio (LMR) and the modified Systemic Inflammatory Score (mSIS) with post-operative outcomes. RESULTS: A total of 81 patients were included in the analysis. Half were females; mean age was 36 ± 15.54 years. Fifty seven percent (n = 46) were operated in expedited settings, with 23.5% developing post-operative complications. In elective patients, higher pre-operative NLR (P = 0.029) and PLR (P = 0.034) were associated with major post-operative complications, higher NLR (P = 0.029) and PLR (P = 0.034) were associated with re-operation and higher PLR correlated with Clavien-Dindo score (P = 0.032). In patients operated in expedited operations, higher pre-operative NLR (P = 0.021) and lower pre-operative LMR (P = 0.018) were associated with thromboembolic events and higher mSIS was associated with major post-operative complications (P = 0.032). CONCLUSIONS: Blood cell interaction based inflammatory markers confer an association with post-operative complications in CD patients undergoing surgery. These indices may facilitate patient selection and optimization when considering the risks and benefits of surgical interventions.

Low psoas muscle area is associated with postoperative complications in Crohn's disease.

BACKGROUND AND AIMS: Crohn's disease (CD) is associated with increased postoperative morbidity. Sarcopenia correlates with increased morbidity and mortality in various medical conditions. We assessed correlations of the lean body mass marker and psoas muscle area (PMA), with postoperative outcomes in CD patients undergoing gastrointestinal surgery. METHODS: We included patients with CD who underwent gastrointestinal surgery between June 2009 and October 2018 and had CT/MRI scans within 8 weeks preoperatively. PMA was measured bilaterally on perioperative imaging. RESULTS: Of 121 patients, the mean age was 35.98 ± 15.07 years; 51.2% were male. The mean BMI was 21.56 ± 4 kg/m2. The mean PMA was 95.12 ± 263.2cm2. Patients with postoperative complications (N = 31, 26%) had significantly lower PMA compared with patients with a normal postoperative recovery (8.5 ± 2.26 cm2 vs. 9.85 ± 2.68 cm2, P = 0.02). A similar finding was noted comparing patients with anastomotic leaks to those without anastomotic leaks (7.48 ± 0.1 cm2 vs. 9.6 ± 2.51 cm2, P = 0.04). PMA correlated with the maximum degree of complications per patient, according to the Clavien-Dindo classification (Spearman's coefficient = -0.26, P = 0.004). Patients with major postoperative complications (Clavien-Dindo ≥ 3) had lower mean PMA (8.12 ± 2.75 cm2 vs. 9.71 ± 2.57 cm2, P = 0.03). Associations were similar when stratifying by gender and operation urgency. On multivariate analysis, PMA (HR = 0.72/cm2, P = 0.02), operation urgency (HR = 3.84, P < 0.01), and higher white blood cell count (HR = 1.14, P = 0.02) were independent predictive factors for postoperative complications. CONCLUSION: PMA is an easily measured radiographic parameter associated with postoperative complications in patients with CD undergoing bowel resection.

Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy in patients with peritoneal carcinomatosis from colorectal cancer: The prognostic impact of baseline neutrophil-lymphocyte, platelet-lymphocyte and lymphocyte-monocyte ratios.

PURPOSE: In this retrospective analysis we sought to determine if the preoperative neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and lymphocyte-monocyte ratio (LMR) were predictive of both operability and survival in those patients presenting with peritoneal carcinomatosis (PC) from colorectal cancer (CRC) who underwent cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). METHODS: Analysis included all patients admitted between 2009 and 2017 with PC from CRC who were treated with curative intent by CRS-Mitomycin C-HIPEC. Patients were assessed pre- and intra-operatively by the PC index (PCI) and by a completeness of cytoreduction (CC) score with calculation of Kaplan-Meier survival curves and multivariate analysis of prognostic factors. Discrimination was made for NLR >3.5, PLR >168.8 and LMR >4.4. RESULTS: We identified 98 CRC patients undergoing 105 CRS-HIPEC procedures. There were no associations detected between NLR/PLR/LMR and the rates of incomplete or abandoned CRS cases. Overall survival (OS) after CRS-HIPEC was worse with high versus low NLR (19.9 mths vs. 45.7 mths, respectively; P = 0.009) and also with low versus high LMR (27.1 mths vs. 53.2 mths, respectively; P = 0.01). On multivariate analysis, a low LMR (P = 0.008), the preoperative CT PCI value (P = 0.004), poor tumor differentiation (P = 0.023) and the preoperative CEA level (P < 0.001) were all independent variables associated with a worse OS after surgery. CONCLUSIONS: The baseline LMR value may have potential value as a selection tool for CRS-HIPEC in patients with CRC-related PC.

[CYTOREDUCTIVE SURGERY AND HYPERTHERMIC INTRAPERITONEAL CHEMOTHERAPY FOR PERITONEAL CARCINOMATOSIS OF COLORECTAL ORIGIN - FIRST 100 CASES].

BACKGROUND: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is an effective treatment for selected patients with peritoneal carcinomatosis of colorectal origin. We present our experience with the first 100 consecutive cases of this combined treatment. METHODS: CRS/HIPEC procedures were performed between 4/2009-8/2016. HIPEC was initially delivered using the "Open" abdomen technique; beginning in January 2014, HIPEC was delivered using the "Closed" technique. As a chemotherapeutic agent we used Mitomycin-C, perfused for duration of 90 minutes at 41 degrees Celsius. RESULTS: A total of 100 procedures were performed in 94 patients (64% females, median age 62 (22-83) years) with colon (n=89) or rectal (n=5) cancer. Complete cytoreduction (CC score≤1) was achieved in 91 procedures. The average duration of surgery was 7.5±2.3 hours, the median number of organs resected was 2 (0-6) and the median length of hospital stay was 9 (5-101) days. Postoperative complications occurred in 54% of procedures and the incidence of major complications (Clavien-Dindo 3-4) was 12%. Three patients (3%) died within 90 days postoperatively. Higher peritoneal cancer index (PCI) score, higher number of organs resected/anastomoses created and longer duration of surgery were associated with perioperative morbidity (all p≤0.05). The median follow-up period was 2.1 years during which 50 patients died. The median overall survival (OS) and disease free survival were 3.1 years and 10.7 months, respectively; 7 patients survived ≥5 years after surgery. Higher PCI score and occurrence of major postoperative complications were associated with poorer OS. CONCLUSIONS: CRS/HIPEC for peritoneal carcinomatosis of colorectal cancer origin is feasible and safe. This treatment may benefit selected patients in terms of OS.

A Single Tertiary Center 10-Year Experience in the Surgical Management of Gastrointestinal Bezoars.

BACKGROUND: Gastrointestinal (GI) bezoars are the most common foreign bodies causing obstruction in the GI tract. They are frequently seen following upper GI tract surgery and surgical intervention is required often. The aim of this study is to describe the surgical management of GI bezoars. MATERIALS AND METHODS: A retrospective cohort study, including all patients diagnosed with bezoars between May 2008 and May 2017, was conducted. Patient charts were reviewed, and demographics, clinical, surgical, and postoperative data were collected and analyzed. RESULTS: Forty-five patients were included, with a mean age of 62.04 years (Range 18-91). Thirty patients underwent previous surgery (66.6%), most commonly surgical interventions for peptic ulcer disease (22 patients, 73.3%). Obstruction was most common in the ileum (27 patients, 60%). Thirty-nine patients (86.7%) required surgical intervention. Laparoscopy was attempted in 20 patients (51.2%), but conversion to open procedure was required in 11 patients (55%). Postoperative complication rate was 41%. No preoperative factors were found to be correlated with postoperative complications. Postoperative complications were associated with a longer length of stay (P = .006) and a higher readmission rate (P = .04). Patients treated with laparoscopy tended to have a lower BMI (P = .04), less previous surgeries (P = .04), and a bezoar located more proximally (P = .03), however, laparoscopy showed no benefit in complications rate, readmissions, and length of stay. CONCLUSIONS: GI bezoars require surgical intervention at high rates. Postoperative complications are common. Completion of an upper GI endoscopy is important and should be performed at an early stage of management.

Hospital readmission rates and risk factors for readmission following cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal surface malignancies.

BACKGROUND: Cytoreductive surgery and Hyperthermic intra-peritoneal chemotherapy (CRS/HIPEC) for peritoneal surface malignancies is associated with high morbidity. The increased numbers of patients undergoing CRS/HIPEC in recent years mandates risk analysis and quality assurance. However, only scarce data exist regarding causative parameters for readmission. The aim of this study was to assess readmission rates and risk factors associated with readmission. METHODS: A retrospective-cohort study including patients from two high-volume centers who underwent CRS/HIPEC surgery between the years 2007-2016 was performed. Patients' demographics, peri-operative data and readmission rates were recorded. RESULTS: 223 patients were included in the study. The 7 and 30-day readmission rates were 3.5% (n = 8) and 11% (n = 25), respectively. Late readmission rates (up to 90 days) were 11% (n = 25). The most common causes of readmission were surgical related infections (35%), small bowel obstruction (17.5%) and dehydration (14%). Post-operative complications were associated with higher readmission rates (p = 0.0001). PCI score was not associated with higher rates of readmission. CONCLUSION: Readmissions following CRS/HIPEC occur mainly due to infectious complications and dehydrations. Patients following CRS/HIPEC should be discharged after careful investigation to a community based continuing care with access for IV fluid replacement or antibiotics administration when required.

Teaching Laparoscopic Adrenalectomy to Surgical Residents.

INTRODUCTION: Laparoscopic adrenalectomy is the surgical treatment for various adrenal diseases. The procedure is a common surgical practice for urologists and general surgeons and requires fundamental laparoscopic skills, nowadays common in the surgical education of residents in these practices. The aim of this study is to assess whether laparoscopic adrenalectomy differs in outcome between certified and trained surgeons and surgical residents and whether the learning curve changes the endpoint of the surgery. MATERIALS AND METHODS: A cohort retrospective study, including all adult patients who underwent laparoscopic adrenalectomy between June 2008 and June 2014, was conducted. Patients' demographic, clinical, and surgical data were recorded and analyzed. RESULTS: Fifty-three patients were included in the database (21 men, 32 women) with a mean age of 54 years (range 17-77). The cause for surgery was most commonly a benign adrenal tumor (27 patients, 50.9%) followed by large nonfunctioning adrenal tumors (16 patients, 30.1%), and adrenal cancer (8 patients, 15%). Eighteen patients (33.9%) were operated by residents (4-6 years into the residency) and 35 patients by a certified senior surgeon (66.1%). Left-sided adrenalectomy was preferred to right-sided adrenalectomy for resident tutoring (P = .03). Overall, intraoperative complications were seen in 6 patients (11.3%) and postoperative complications were seen in 9 patients (16.9%). There were no differences in operation time (P = .36), intraoperative complications (P = .76), postoperative complications (P = .96), and length of stay (P = .34) between the patients operated by senior residents and certified surgeons. CONCLUSION: Laparoscopic adrenalectomy is a complex surgical procedure that should be a part of the surgical training of surgery residents, as it is safe in guided hands.

Autosomal recessive hyponatremia due to isolated salt wasting in sweat associated with a mutation in the active site of Carbonic Anhydrase 12.

Genetic disorders of excessive salt loss from sweat glands have been observed in pseudohypoaldosteronism type I (PHA) and cystic fibrosis that result from mutations in genes encoding epithelial Na+ channel (ENaC) subunits and the transmembrane conductance regulator (CFTR), respectively. We identified a novel autosomal recessive form of isolated salt wasting in sweat, which leads to severe infantile hyponatremic dehydration. Three affected individuals from a small Bedouin clan presented with failure to thrive, hyponatremic dehydration and hyperkalemia with isolated sweat salt wasting. Using positional cloning, we identified the association of a Glu143Lys mutation in carbonic anhydrase 12 (CA12) with the disease. Carbonic anhydrase is a zinc metalloenzyme that catalyzes the reversible hydration of carbon dioxide to form a bicarbonate anion and a proton. Glu143 in CA12 is essential for zinc coordination in this metalloenzyme and lowering of the protein-metal affinity reduces its catalytic activity. This is the first presentation of an isolated loss of salt from sweat gland mimicking PHA, associated with a mutation in the CA12 gene not previously implicated in human disorders. Our data demonstrate the importance of bicarbonate anion and proton production on salt concentration in sweat and its significance for sodium homeostasis.