Effects of thyroid hormone on the adaptation in short bowel syndrome.

BACKGROUND: Thyroid hormone acts on structural and functional maturation of the mammalian small intestine, mitochondrial pathways, and several protein-gene interactions. Therefore, it is one of the most important regulators of intestinal epithelial differentiation. The aim of the study was to evaluate the effects of thyroid hormone on the adaptation in an experimental model of short bowel syndrome. METHODS: Rats were divided into three groups: sham (bowel transection and anastomosis), short bowel syndrome-saline (75% bowel resection and anastomosis), and short bowel syndrome-thyroid hormone (75% bowel resection and anastomosis, and was administered triiodothyronine). The evaluation of adaptation parameters, histopathological and biochemical analysis were performed in all groups. RESULTS: Triiodothyronine treatment resulted in a significant increase in adaptation parameters, villus height-crypt depth, and enterocyte proliferation, whereas significant decrease was seen in apoptotic index in jejunum. Enterocyte proliferation and most of the adaptation parameters changed significantly in ileum following the treatment with triiodothyronine as in jejunum. The changes in ileal villus height-crypt depth and apoptotic index were not statistically significant. Serum levels of free triiodothyronine were lower in the short bowel syndrome-saline group. CONCLUSIONS: Our results suggest that thyroid hormone treatment in the hypothyroid phase of SBS enhances intestinal adaptive response.

The timing of laparoscopic cholecystectomy after endoscopic retrograde cholangiopancreaticography in cholelithiasis coexisting with choledocholithiasis.

BACKGROUND: An accepted treatment strategy for cholelithiasis with secondary choledocholithiasis is the laparoscopic cholecystectomy (LC) following endoscopic retrograde cholangiopancreaticography (ERCP). Although early cholecystectomy is advised, there is no consensus about the time interval between LC and ERCP. The aim of this study is to evaluate the effects of the time interval between ERCP and ERCP on operation outcomes. METHODS: Patients with cholelithiasis and a risk of choledocholithiasis underwent ERCP. Patients were grouped as those operated on between 24 and 72 h after ERCP (group 1) and those operated on more than 72 h after ERCP (group 2). Patients' age, gender, body mass index, American Society of Anesthesiologists Physical Status, abdominal ultrasonography findings, white blood cell count, total serum bilirubin, ALP, amylase, ALT, AST, GGT levels, ERCP findings, time interval between ERCP and LC, conversion rate, median postoperative hospital stay, median operation time, intraoperative complication and postoperative complication rates were collected. RESULTS: There was no significant difference between the demographics of the patients in both groups. The median operation time, median postoperative hospital stay and conversion rate in group 2 were significantly higher than those of group 1. More postoperative complications were seen in group 2. CONCLUSION: Early cholecystectomy after ERCP, within 72 h, has better outcomes, probably due to the inflammatory processes.

Leptin treatment ameliorates acute lung injury in rats with cerulein-induced acute pancreatitis.

AIM: To determine the effect of exogenous leptin on acute lung injury (ALI) in cerulein-induced acute pancreatitis (AP). METHODS: Forty-eight rats were randomly divided into 3 groups. AP was induced by intraperitoneal (i.p.) injection of cerulein (50 microg/kg) four times, at 1 h intervals. The rats received a single i.p. injection of 10 mug/kg leptin (leptin group) or 2 mL saline (AP group) after cerulein injections. In the sham group, animals were given a single i.p. injection of 2 mL saline. Experimental samples were collected for biochemical and histological evaluations at 24 h and 48 h after the induction of AP or saline administration. Blood samples were obtained for the determination of amylase, lipase, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, macrophage inflammatory peptide (MIP)-2 and soluble intercellular adhesion molecule (sICAM)-1 levels, while pancreatic and lung tissues were removed for myeloperoxidase (MPO) activity, nitric oxide (NOx) level, CD40 expression and histological evaluation. RESULTS: Cerulein injection caused severe AP, confirmed by an increase in serum amylase and lipase levels, histopathological findings of severe AP, and pancreatic MPO activity, compared to the values obtained in the sham group. In the leptin group, serum levels of MIP-2, sICMA-1, TNF-alpha, and IL-1beta, pancreatic MPO activity, CD40 expression in pancreas and lung tissues, and NOx level in the lung tissue were lower compared to those in the AP group. Histologically, pancreatic and lung damage was less severe following leptin administration. CONCLUSION: Exogenous leptin attenuates inflamma-tory changes, and reduces pro-inflammatory cytokines, nitric oxide levels, and CD40 expression in cerulein-induced AP and may be protective in AP associated ALI.

A prospective comparison of local and spinal anesthesia for inguinal hernia repair.

AIM: Today, in inguinal hernia repair, postoperative pain and costs are regarded as equally important issues as technique and recurrence rates. Postoperative pain is thought to vary according to the applied anesthesia method. As local anesthesia is reported to inflict less pain, its effects on early period post-operative complications should also be evaluated. METHODS: Two hundred patients, on whom Lichtenstein tension free hernia repair had been performed due to unilateral inguinal hernia between March 2004 and July 2005, were prospectively examined. The patients were randomized according to the anesthesia applied. They were divided into two groups: local anesthesia (LA) and spinal anesthesia (SA). The early post-operative complications, post-operative pain scores, and operation durations of the patients, were evaluated. RESULTS: Local anesthesia was found not to increase the post-operative complications; on the contrary, it was shown to prevent the complications of spinal anesthesia. Although visual analogue pain score (VAS) values at 4, 8, 12, and 24 h post-operation were found to be lower than the SA group, the difference between was not significant. Also, it was discovered that LA did not retard the operation duration. CONCLUSION: Local anesthesia reduces post-operative pain and facilitates patients' mobilization and discharge along with decreasing the early post-operative complications. Thus, LA is a safe and advantageous method to be applied in inguinal hernia repair.

Strangulation of a prolapsed rectal cancer in labor: a case report.

BACKGROUND: Colorectal cancer during pregnancy is uncommon. Most patients present in late pregnancy, and the tumor is localized to rectum in up to 85% of cases. Delayed diagnosis due to confusing significant lower gastrointestinal symptoms with pregnancy-associated gastrointestinal changes is a common feature. From the increasing intraabdominal pressure during delivery, a tumor can prolapse throu the anus and develop incarceration and strangulation, but that is seen a extremely rarely, CASE: A 33-year-old woman was found to have a prolapsing rectal cancer through the anus during delivery, and it progressed to incarceration, CONCLUSION: Colorectal cancer during pregnancy is rare and mostly localized to the rectum. To manage a strangulated rectal prolapse that occurs in labor, consideration should be given to perineal rectosigmoidectomy under general anesthesia. The choice of surgical procedure is controversial if the preoperative diagnosis is not clear.

[Hepatic portal venous gas: a case report]. / Hepatik portal vende gaz: olgu sunumu.

Gas in hepatic portal vein is a rare entity. This may be apparent after mesenteric ischemia, blunt abdominal trauma, intestinal obstruction, and intra-abdominal infection. Intrahepatic gas was detected by direct abdominal graphy in a 58 year-old man who was admitted to our emergency service with acute abdomen. On computed tomography; portal vein gas, pneumatosis intestinalis, and occlusion of superior mesenteric vein and artery were detected. The patient who had had significant concomittant operative risks, died prior to surgery. Gas in portal vein is a good predictive factor for diagnosis, management, and prognosis. This sign may avoid unnecessary surgery and also it may help to make an early decision for surgery.

The effect of platelet activating factor antagonist BN 52021 on bacterial translocation and ICAM-I expression in experimental obstructive jaundice.

Expression of intracellular adhesion molecule-1 (ICAM-1) in an obstructive jaundice model and the potential protective role of platelet activating factor antagonist over small intestine and liver together with its effects on bacterial translocation are examined in this study. Forty-eight male Wistar albino rats were assigned into four equal groups of 12. In groups I and II, animals were sham operated. In groups III and IV, common bile duct ligation and division were performed. In group I and group III, 0.5 ml/day normal saline was applied intraperitoneally daily from day 2 to 6 of the study; in group II and group IV, 1 mg/kg/day BN 52021 was applied intraperitoneally daily from day 2 to 6 of the study. All animals were sacrificed on postoperative day 7. ICAM-1 expression (CD54 positivity) was analyzed in the liver and ileum tissue by immunohistochemical method. Samples from blood, liver mesenteric lymph nodes, and spleen were cultured under aerobic conditions. It is revealed that ICAM-1 expression was statistically higher in group III, with highest bacterial translocation and liver and spleen injury when compared to other groups. Serum alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), gamma-glutamyltranspeptidase (GGT), bilirubin, tumor necrosis factor alpha (TNFalpha), and interleukin 1beta(IL-1beta) values were at the highest level in group III, and there was a statistical decrease in group IV compared to group III. The administration of BN52021 in experimental obstructive jaundice is a useful way to reduce liver and intestinal mucosal villi damage by inhibiting bacterial translocation and systemic inflammatory response.

Management of acute calculous cholecystitis in high-risk patients: percutaneous cholecystotomy followed by early laparoscopic cholecystectomy.

Emergency cholecystectomy for acute cholecystitis is associated with high morbidity and mortality rates in patients with significant comorbidities and high-risk surgery. The aim of this study was to evaluate the effectiveness, possible advantages, and complications of percutaneous cholecystostomy (PC) followed by an early laparoscopic cholecystectomy (LC) in relation to conservative treatment followed by a delayed LC in high-surgical risk patients. Between 2002 and 2004, patients were randomly classified into 2 groups: the first group consisted of patients who had PC followed by an early LC (PCLC group, n = 31) and the second group consisted of patients who had conservative treatment followed by a delayed LC (DLC group, n = 30). The groups were statistically compared regarding their demographic, comorbidity, hospital stay, conversion, and complication rates. PC was technically successful in 31 patients with no attributable mortality or major complications. No difference had been found in regarding demographic, comorbidity, and complication rates. In PCLC group, all the patients experienced symptom relief within 24 hours, and early LC was attempted in 31 patients once their clinical condition was sufficiently stable, this was successfully accomplished in 29 (93.5%). In the DLC group, delayed LC was attempted in 30 patients, and this was successfully accomplished in 26 (86.6%). The hospital stay was shorter and cost was in the PCLC group was lower than in the DLC group. PC allows resolution of sepsis in patients at high surgical risk. Early LC could be safely performed once sepsis and acute infection resolved in these patients.

Laparoscopic cholecystectomy in patients with previous abdominal surgery.

BACKGROUND: Laparoscopic cholecystctomy has become the treatment of choice for symptomatic gallstones. The potential risks have dissuaded some surgeons from using the laparoscopic procedure in patients with previous abdominal surgery. Therefore, we aimed to investigate the effect of previous abdominal surgery on the feasibility and safety of laparoscopic cholecystectomy. METHODS: This study included 600 well-documented patients with gallstones who underwent laparoscopic cholecystctomy at our surgical department between May 2000 and January 2004. The patients were classified into 3 groups: group 1, patients without a history of previous abdominal surgery (n = 408); group 2, patients with a history of upper abdominal surgery (n = 92); group 3, patients with a history of lower abdominal surgery (n = 100). The data were collected and analyzed for open conversion rates, operative times, perioperative and postoperative complications, and hospital stay. RESULTS: Of the 600 study patients, 192 had undergone previous abdominal surgery (92 upper, 100 lower). Conversion rate, hospital stay, and complication rates were similar in each group. Mean operating time was the longest (57 +/- 9.8 min) in patients with previous upper abdominal surgery (P < 0.05). On the other hand, the operative time was similar in groups 1 and 3 (P > 0.05). CONCLUSION: Previous abdominal surgery is not a contraindication to safe laparoscopic cholecystectomy. However, previous upper abdominal surgery is associated with a prolonged operation time.

Timing of laparoscopic cholecystectomy for subacute calculous cholecystitis: early or interval--a prospective study.

BACKGROUND/PURPOSE: The aim of this prospective study was to evaluate the safety and feasibility of early laparoscopic cholecystectomy for subacute cholecystitis and to compare it with interval laparoscopic cholecystectomy. METHODS: The study was performed in 74 patients who had been diagnosed with subacute cholecystitis between January 2000 and June 2005. The patients were divided into two groups. The early laparoscopic cholecystectomy group was composed of 31 patients who underwent laparoscopic cholecystectomy 24 h after admission to the hospital. The interval laparoscopic cholecystectomy group was composed of 43 patients who underwent laparoscopic cholecystectomy 8-12 weeks after medical treatment. RESULTS: There was no significant difference between the conversion rate, intraoperative bleeding, need for intraoperative cholangiography, minor bile duct injury, and postoperative complications in the two groups. Eleven patients in the interval group underwent urgent laparoscopic cholecystectomy or additional procedures because of recurrent cholecystitis, choledocholithiasis, or biliary pancreatitis. The early group had a significantly shorter total hospital stay (P = 0.031), lower cost of treatment (P = 0.042), and less difficulty with Calot's triangle dissection (P = 0.008). CONCLUSIONS: Early laparoscopic cholecystectomy can be done without hesitation in patients with subacute cholecystitis, in the light of obstacles observed in the interval group, such as dissection difficulty, lack of success in "cooling down", and additional problems such as choledocholithiasis and biliary pancreatitis.

Ultrasonography in the diagnosis of true gallbladder polyps: the contradiction in the literature.

Polypoid lesions of the gallbladder (PLGs) are often incidentally identified during ultrasonographic examination of abdominal pain. The present study was designed to determine the reliability of ultrasonography (US) in the diagnosis of PLGs. The records of 853 patients who underwent laparoscopic cholecystectomy (LC) for PLGs in Gazi Medical School from January 2000 to January 2004 were reviewed. Data were collected regarding the patients' gender, age, symptoms, serum lipid levels, the size and the number of polyps on US, surgical indications for PLGs and histopathological diagnosis. In all, 56 of 853 patients had PLGs and underwent LC. Right upper quadrant pain (59%) was the most common presenting symptom that led to gallbladder US. Nearly 75% of the lesions were smaller than 10 mm. At histopathologic examination cholesterolosis was found in 17 of 56 (30%) patients, and 12 of 56 (21%) demonstrated only cholelithiasis; 17 (30%) patients had both cholesterolosis and stones. Only 10 (18%) patients had adenomatous polyp and 8 of these polyps were larger than 1 cm. Overall US-based diagnosis of gallbladder polyp was inaccurate in 82%. The sensitivity and specificity of US for polyps <1 cm was 20% and 95.1%, respectively, whereas the sensitivity and specificity of US for polyps >1 cm was 80% and 99.3%, respectively. The accuracy of US in diagnosing PLGs was poor, especially in polyps <1 cm.

Urgent laparoscopic cholecystectomy is the best management for biliary colic. A prospective randomized study of 75 cases.

BACKGROUND/AIM: Delay of laparoscopic cholecystectomy after the diagnosis of biliary colic may increase the probability of recurrent emergency admission while awaiting elective cholecystectomy. The aim of this study was to compare the possible advantages and safety of urgent laparoscopic cholecystectomy (ULC) with elective laparoscopic cholecystectomy (ELC) in patients with biliary colic. PATIENTS AND METHODS: Between 2001 and 2003, 75 patients with biliary colic were included in this study. The patients were classified into following two groups: patients who had ULC in 24 h were in group I (n = 28) and patients who had ELC (mean interval 4.22 +/- 1.42 months) were in group II (n = 35). Conversion to open cholecystectomy, operative time, postoperative hospital stay, costs, and complications were evaluated. RESULTS: In group II, 9 patients made a total of 13 return visits to the emergency department with recurrent attacks of biliary colic or complications of gallstone disease. Mean operative time increased from 35.1 +/- 6.74 min for urgent laparascopic cholecystectomy to 49.9 +/- 6.12 min for ELC (p > 0.05) and hospital stay time increased from 1.06 +/- 0.4 to 2.31 +/- 2.36 days (p < 0.05). Conversion to open cholecystectomy increased from 0% in group I to 17.2% in group II (p < 0.05). DISCUSSION: ULC for biliary colic may be the most medically efficacious and cost-effective treatment.

Comparison of botulinum toxin injection and lateral internal sphincterotomy for the treatment of chronic anal fissure.

PURPOSE: Botulinum toxin injection into the internal anal sphincter has been shown to be an effective treatment for chronic anal fissure. A randomized, prospective trial was conducted to compare botulinum toxin with lateral internal anal sphincterotomy as definitive management for chronic anal fissure. METHODS: Patients diagnosed as having chronic anal fissure were randomly assigned to one of the two treatment arms. In the botulinum toxin group (n = 61), 20 to 30 U (approximately 0.3 U/kg) of type A botulinum toxin (Botox) was injected into the internal anal sphincter. The injection was repeated two months later if complete healing was not accomplished. Patients in the sphincterotomy group (n = 50) underwent lateral internal anal sphincterotomy. The same investigators evaluated the patients on postoperative/postinjection days 7 and 28, and then in a blinded manner at 2, 6, and 12 months. RESULTS: In the botulinum group, single injection resulted in complete healing in 45 of the 61 patients (73.8 percent) at the second month. Of the 16 failures, 6 patients refused further treatment, and 10 were treated with a second injection, which resulted in an overall healing rate of 86.9 percent (53/61) at 6 months. In the sphincterotomy group, the success rate was 82 percent (41/50) at day 28 and 98 percent (49/50) at the second month (P = 0.023 and P < 0.0001, respectively, compared with the botulinum group-single injection). At 6 months, 2 patients in the LIS group developed recurrences, and the healing rate was similar to that of the botulinum group (86.9 96.4 percent; P = 0.212). At 12 months, the success rate of the Botox group fell to 75.4 percent (46/61) with 7 recurrences, whereas it remained stable in the sphincterotomy group (94 percent, P = 0.008). Sphincterotomy was associated with a significantly higher complication rate (8 cases of anal incontinence none in the botulinum toxin group; P < 0.001). Full return to daily activities took significantly less time in the botulinum group (1 14.8 +/- 5.7 days; P < 0.0001). CONCLUSION: Although the healing rate of chronic anal fissure is considerably high with botulinum toxin injection with earlier recovery and less complications compared with sphincterotomy, it occasionally requires a repeat injection, and the healing is slower. The early (two months) and late (one year) healing rates are significantly higher in the sphincterotomy group, the two groups reaching similar healing rates only at six months.

Unexpected gallbladder cancer during laparoscopic cholecystectomy.

BACKGROUND/PURPOSE: In the present study, we investigated the effectiveness of surgeons in determining incidental gallbladder pathologies at laparoscopic cholecystectomy (LC). METHODS: This study included 548 patients with gallstones who underwent LC between May 1, 2001 and October 15, 2003. The surgeon made an incision on the gallbladder wall for inspection, and palpated the mucosa after removing the gallbladder from the abdominal cavity to look for unsuspected pathologies. If an abnormal mucosa was observed or palpated, it was marked with a silk suture and then histopathologic examination was performed. RESULTS: Fifty of 548 LC specimens were found to be suspi-cious by the surgeon. Histopathological examination of frozen sections revealed incidental pathologies in 15 of these specimens. Strikingly, 5 of these specimens were considered to have gallbladder cancer (GBC). The other incidental pathologies were consistent with adenomyomatosis, xanthogranulomatous cholecystitis, and fibroepithelial and hyperplastic polyps. Four of the other 498 specimens revealed incidental pathologies at definitive histopathological examination, and all of them were consistent with gastric metaplasia. The sensitivity and specificity of the procedure was 78.9% and 93%, respectively. CONCLUSIONS: A simple prosedure; that is, incision and inspection, and palpation of the gallbladder, seems to be useful for the diagnosis of incidental gallbladder pathologies.

Modified Limberg transposition flap for sacrococcygeal pilonidal sinus.

PURPOSE: To investigate the results of wide rhomboid excision with Limberg transposition flap reconstruction to treat pilonidal sinus. METHODS: We analyzed the well-documented records of 238 patients with sacrococcygeal pilonidal sinus who underwent wide excision with a Limberg transposition flap and were followed up for longer than 1 year postoperatively. After the first 40 operations, we modified this flap reconstruction by tailoring the rhomboid excision asymmetrically to place the lower pole of the flap 1-2 cm lateral to the midline. Wound infection rates, hospitalization, time required for free mobilization, and recurrence rates were recorded. RESULTS: Postoperative infection developed in two patients (0.8%), which was easily managed by wound care, antibiotics, removal of skin staples, prolonged drainage, or a combination of these treatments. The mean hospitalization was 2.10 +/- 0.20 days (range 1-3 days), and the mean time required for recovery and return to daily activities was 8.00 +/- 2.50 days (range 4-17 days). There were only three recurrences (1.26%) after a mean follow-up of 29.20 +/- 3.10 months (range 12-38 months). Since we started performing our modification of the technique by lateralization of the inferior apex, no further recurrences have been seen. The recurrence rate differed significantly between the classical Limberg flap group and the modified Limberg flap group ( P = 0.004) CONCLUSION: These results provide further evidence that wide excision with a Limberg transposition flap reconstruction is an effective surgical method for primary or recurrent pilonidal sinus, associated with a low complication rate, short hospitalization and disability, and a low recurrence rate. A modification of the technique was devised to further enhance wound healing and reduce the risk of recurrence.

Effect of mucosal immunomodulation with fed cholera toxin on healing of experimental colonic anastomosis.

PURPOSE: The aim of this study was to investigate in rats whether preoperative orogastric administration of low doses of cholera toxin would influence the mechanical strength of experimental colonic anastomosis on the basis of the gut mucosal immunomodulation effect of this antigen. METHODS: The cholera toxin group (n = 14) was fed 10 microg of cholera toxin in phosphate-buffered saline three times before surgery at 10-day intervals, whereas the controls (n = 14) received phosphate-buffered saline only. Twenty-four hours after the last dose of cholera toxin (or placebo in control group), the animals underwent left colonic transection and anastomosis. Seven days after colonic transection-anastomosis, the bursting pressure of the anastomotic segment was recorded in situ. Perianastomotic and extra-anastomotic tissue samples were obtained for measurements of tissue transforming growth factor-beta, interleukin-6, and interferon-gamma levels with enzyme-linked immunosorbent assay. RESULTS: Cholera toxin administration resulted in a significantly higher bursting pressure than in the control group (165.78 +/- 12.37 vs. 138.4 +/- 7.87 mmHg; P < 0.001). Compared with the control group, the heightened mechanical strength of colonic anastomosis provided by cholera toxin was associated with significant increases in the perianastomotic tissue levels of transforming growth factor-beta (199.34 +/- 24.85 vs. 70.66 +/- 10.63 pg/ml; P < 0.001) and interleukin-6 (439.31 +/- 95.14 vs. 289.57 +/- 96.59 pg/ml; P = 0.001), whereas interferon-gamma was significantly lower (174.04 +/- 44.82 vs. 219.00 +/- 31.35 pg/ml; P < 0.05). This cytokine pattern induced by cholera toxin in the wound milieu was also found to be similar in the extra-anastomotic colon. CONCLUSION: The mechanical strength of uncomplicated experimental colonic anastomosis increased significantly with gut mucosal immunomodulation with repeated low preoperative doses of cholera toxin. This enhanced healing had significant positive correlation with the colonic tissue level of transforming growth factor-beta and inverse correlation with interferon-gamma. If the relevant dose regimen is identified and its safety is assured in humans, gut mucosal immunomodulation might provide an efficient, safe, and inexpensive tool to improve surgical outcome in colorectal surgery, particularly in high-risk situations.

Clinical approach to graft hepatic artery thrombosis following living related liver transplantation.

Hepatic artery thrombosis (HAT) has an occurrence rate of 1.7-26% following living donor liver transplantation (LDLT) and is one of the most common reasons for graft loss and mortality in this population. There is a higher incidence of HAT in pediatric recipients. The aim of this case report is to discuss clinical approaches for the treatment of HAT occurring in the early post-operative period after LDLT. An 11-month-old, 7.8-kg female with cirrhosis secondary to biliary atresia underwent LDLT at Gazi University Hospital in Ankara. The graft was a left lateral segment from her father with a left hepatic artery (HA) of 2 mm diameter and a graft weight/recipient body weight ratio of 2.0%. After an uneventful early post-operative period, HAT was diagnosed by Doppler ultrasonography (USG) on the fifth post-operative day. Following angiographic evaluation, immediate exploration and reanastomosis was performed using an operation microscope. Post-operatively, the HA was patented by Doppler USG and graft function returned to normal. Now, 42 months later, the patient continues to do well with normal graft function, using a regimen of tacrolimus monotherapy for immunosuppression. In countries which have very limited resources for urgent re-transplantation, given their serious donor shortage, graft salvage may be the only option for patient survival when HAT occurs. In these circumstances, early diagnosis and immediate revascularization may be the only method for graft salvage. A daily routine of Doppler USG examination in the early post-operative period may provide a method for the early diagnosis of HAT, before liver enzymes are elevated and hepatic necrosis has begun.