Bacterial Translocation in Acute Pancreatitis

Journal of Gastroenterology and Hepatology (2003) 18, 1214–1224

Blackwell Science, LtdOxford, UKJGHJournal of Gastroenterology and Hepatology0815-93192003 Blackwell Publishing Asia Pty LtdOctober 2003181012141224Letter to the EditorLetters to the EditorLetters to the Editor

© 2003 Blackwell Publishing Asia Pty Ltd

LETTERS TO THE EDITOR

BACTERIAL TRANSLOCATION INACUTE PANCREATITIS

To the Editor,Wang et al.1 open the abstract of their article with thestatement, ‘Gut-origin bacterial translocation is one ofthe major causes of pancreatic necrotic tissue infectionin patients with severe acute pancreatitis (SAP)’.Although the profile of organisms isolated from necroticpancreatic tissue is similar to that of the gut, there isminimal evidence to support the occurrence of bacterialtranslocation in humans.2

The references cited by the author in the body of thearticle3,4 refer to animal studies. The clinical significanceof the impairment in motility, which was elegantly,although not surprisingly, demonstrated by the authorsis thus open to question. If an enteral source of organ-isms is important in the pathogenesis of pancreaticnecrotic tissue infection, one would suspect that selec-tive decontamination of the gut early in an episode ofacute pancreatitis, or even prophylactically in patients athigh risk of developing pancreatitis, would be effica-cious. Evidence for this is again minimal, although onemulticenter study5 showed a lower pancreatic infectionrate and a trend towards a lower mortality in a random-ized controlled clinical trial in patients with severe acutepancreatitis who received oral and rectal colistin,amphotericin and norfloxacin. However, the findings ofthis study are difficult to interpret in view of the factthat patients in the ‘decontamination’ group were alsogiven intravenous cefotaxime until bacteria had beeneliminated from the oral cavity and rectum.

Andrew ThomsonGastroenterology Unit, The Canberra Hospital,

Canberra, Australia

REFERENCES

1 Wang XP, Gong Z, Wu K, Wan BX, Yuang AZ. Gastroin-tetsinal dysmotlity in patients with acute pancreatitis. J.Gastroenterol. Hepatol. 2003; 18: 57–62.

2 Jeejeebhoy K. Total parenteral nutrition: potion or poi-son? Am. J. Clin. Nutr. 2001; 74: 160–3.

3 Wang XP, Wang BS, Wu JX, Wang GL. Beneficial effectsof growth hormone on bacterial translocation during thecourse of acute nectrotizing pancreatitis in rats. Pancreas2001; 23: 148–56.

4 Moody FG, Haley–Russell D, Muncy DM. Intestinaltransit bacterial translocation obstructive pancreatitis.Dig. Dis. Sci. 1995; 40: 1798–804.

5 Luiten EJ, Hop WCJ, Lange JF, Bruining HA. Controlledclinical trial of selective decontamination for the treatmentof severe acute pancreatitis. Ann. Surg. 1995; 222: 57–65.

Blackwell Science, LtdOxford, UKJGHJournal of Gastroenterology and Hepatology0815-93192003 Blackwell Publishing Asia PtyLtdOctober 2003181012141215Letter to the EditorLetters to the EditorLetters to the Editor

ASEPTIC SUBCUTANEOUSABSCESS ASSOCIATED WITHULCERATIVE COLITIS

To the Editor,Ulcerative colitis (UC) is a chronic inflammatory disor-der of presumed autoimmune etiology. It can some-times be associated with various types of skin diseases,such as erythema nodosum and pyoderma gangreno-sum. The coexistence of UC and aseptic subcutaneousabscess has been extremely rare. We report herein anunusual case of a patient who initially suffered from UCand subsequently developed aseptic subcutaneousabscess.

A 34-year-old Japanese woman, with a three-year his-tory of left-sided UC, presented with exacerbation ofhematochezia with a five-day duration of fever, arthral-gia in the right elbow and knee joints, and pain in thesternal region. On admission, there was marked tender-ness on the sternum, but no skin lesions. Pulmonaryand cardiac examination was unremarkable. Labora-tory parameters revealed a white blood cell count of8.4 ¥ 109/L and elevated C-reactive protein level(7.7 mg/dL). During the hospital course, a painful sub-cutaneous mass developed on the sternum (Fig. 1a).

There was no acne around the lesion. Computedtomography (CT) of the chest disclosed a 4 cm ovalhomogenous low-density abscess on the sternum, butno osteomyelitis in the sternum (Fig. 1b). Bone scinti-gram was negative. Incision of the abscess yielded ster-ile. Diagnosis of aseptic subcutaneous abscess of thesternal region was made. Her bowel, joint and cutane-ous lesions resolved with prednisolone. Six weeks later,however, a similar painful abscess reappeared on thesame region with exacerbation of neither colitis norarthralgia. Puncture drainage and prednisolone wereeffective. Culture of the abscess was negative. Thepatient has not exhibited aseptic abscess since this time.

Subcutaneous abscess in the present case did notform ulceration, thus it was not considered to be pyo-derma gangrenosum. Our patient had two episodes ofaseptic subcutaneous abscess within six weeks. The firstoccurred parallel to the exacerbation of colitis, but thesecond episode did not coincide. There have been a fewreported cases of recurrent aseptic subcutaneousabscess associated with UC.1,2 Murata et al. reported apatient with an abscess related to osteomyelitis of thesternum, thus the diagnosis of synovitis-acne-pustulosishyperostosis-osteomyelitis (SAPHO) syndrome wasmade.1 Our patient demonstrated a similar clinicalcourse to the latter case who had no osteomyelitis.2

Erythema nodosum and pyoderma gangrenosumhave been well-recognized cutaneous complications ofUC.3 A possible link with the cross-reactive protein(s) inthe immunopathogenesis of ulcerative colitis, sclerosing

Letters to the Editor 1215

Figure 1 (a) Subcutaneous abscess on the chest. (b) Com-puted tomography of the chest showed (Æ) an abscess on thesternum without osteomyelitis.

a

b

cholangitis, and pyoderma gangrenosum has been pre-sumed, because the skin and biliary tract epithelial cellswere reported to share a unique epitope on colonic epi-thelial protein.4 A recent study has indicated that somepatients with UC and Crohn’s disease have an IgGautoantibody to the epidermolysis bullosa acquisitaantigen (type VII collagen), which exists in both the skinand the gut.5 Therefore, the coexistence of exacerbationof UC and aseptic subcutaneous abscess in this case maybe coincidental, or because of cross reactivity betweencertain autoantigen(s) shared by the colon and skin.

In conclusion, aseptic subcutaneous abscess mayaccompany UC as an extraintestinal manifestation.Cutaneous lesions should be carefully assessed in themanagement of UC.

Fukunori Kinjo,Shiro Miyazato,Akira Hokama,Yukino Kugai,Atsushi Saito

First Department of Internal Medicine, University of theRyukyus, Okinawa, Japan

REFERENCES

1 Murata I, Satoh K, Yoshikawa I et al. Recurrent subcuta-neous abscess of the sternal region in ulcerative colitis.Am. J. Gastroenterol. 1999; 94: 844–5.

2 Hara H, Wakui F, Fujitysuka A et al. Subcutaneousabscess in a patient with ulcerative colitis. J. Am. Acad.Dermatol. 2000; 42: 363–5.

3 Farmer RG. Ulcerative colitis. Complications. In:Haubrich WS, Schaffner F, Berk JE, eds. Bochus Gastro-enterology 5th edn. Philadelphia: W.B. Saunders, 1995;1357–63.

4 Das KM, Vecchi M, Sakamaki S. A shared and uniqueepitope(s) on human colon, skin, and biliary epitheliumdetected by a monoclonal antibody. Gastroenterology 1990;98: 464–9.

5 Chen M, O’Toole EA, Sanghavi J et al. The epidermolysisbullosa acquisita antigen (type VII collagen) is present inhuman colon and patients with Crohn’s disease haveautoantibodies to type VII collagen. J. Invest. Dermatol.2002; 118: 1059–64.


ENDOSCOPIC HEMOSTASIS FOR RADIATION-INDUCED GASTRITIS USING ARGON PLASMA COAGULATION

To the Editor,Radiation-induced gastritis is a rare disorder causinguncontrollable hemorrhage. We encountered two pati-ents with hemorrhagic gastritis induced by externalradiotherapy for biliary tract cancers located at thehepatic hilus. Initially, the patients required frequentblood transfusion, but their condition improved dra-matically after endoscopic treatment using argonplasma coagulation (APC).

A 60-year-old woman was referred for evaluation andtreatment of gallbladder cancer. Because computedtomography (CT) showed massive tumor invasion ofthe portal vein, the patient was treated with fractionatedexternal beam radiotherapy (60 Gy) applied to the gall-bladder cancer and bile duct at the hepatic hilus.Patency of the bile duct improved and two self-expand-ing metallic stents (EMS) were inserted. Four monthsafter radiotherapy, laboratory evaluation revealed severeanemia and the patient was hospitalized immediately.Gastroscopy showed multiple telangiectasias confinedto the antrum, with oozing of blood from the mucosa(Fig. 1a). She was diagnosed with hemorrhagic radia-tion-induced gastritis. APC (APC-300; ERBE) wasperformed via an endoscope (Fig. 1b). Coagulationwas carried out at an output of 60 W and a flow rate of2 L/min. After APC, red blood cell counts stabilized.Anemia was alleviated temporarily by blood transfu-sion, but worsened over several days. Gastroscopyrepeated one week after the first procedure revealedulcer formation in the area treated by APC (Fig. 1c).Additional APC was performed for the remainingtelangiectasia (Fig. 1d). Gastroscopy one week after thesecond APC showed shallow ulcer and disappearance oftelangiectasia (Fig. 1e). The patient was dischargedfrom the hospital and gastroscopy 3 months after APCshowed ulcer scars and mild telangiectasia that were nothemorrhagic (Fig. 1f). Only one additional blood trans-fusion was required in the following months. She died

1216 Letters to the Editor

Figure 1 Argon plasma coagulation (APC) therapy for hemorrhagic radiation-induced gastritis. (a) Multiple patchy areas oftelangiectasia extend over the antrum. (b) Area cauterized by APC shows black discoloation. (c) One week after the first APC,the coagulated area shows ulceration. (d) Additional APC is carried out for remaining telangiectasia. (e) One week after the sec-ond APC, telangiectasia has disappeared. (f ) Three months after APC, only minimal telangiectasia is present with no bleedingtendency.

of peritoneal carcinomatosis 6 months after APC(Fig. 2).

A 65-year-old man with adenocarcinoma of thehepatic hilus was referred for evaluation and treatment.Because CT showed an extensive tumor, he was treatedwith EMS insertion and fractionated external beamradiotherapy (60 Gy). Two months after radiotherapy,the patient developed epigastric pain and anorexia andreturned to hospital. As laboratory evaluation indicatedsevere anemia, he was admitted immediately andreceived a blood transfusion. Gastroscopy showedmultiple punctate telangiectasias in a diffuse antraldistribution. He was diagnosed with hemorrhagic radi-ation-induced gastritis. A total of three APC proceduresarre sted progression of anemia (Fig. 3). The patientwas discharged and did not need a blood transfusionfor 4 months until rehospitalization for peritonealcarcinomatosis.

Many patients with unresectable biliary tract cancerhave been treated with external beam radiotherapy(EBRT) with or without intraluminal radiotherapy. Inour institution, a total dose of 50 Gy of EBRT hadproven to be ineffective in patients with biliary tractcancer. As previously reported, survival was prolonged

by increasing the total dose of EBRT to 58–60 Gy; onesuch patient survived more than 5 years.1 However, twopatients developed hemorrhagic radiation-induced gas-tritis, which we had not encountered when the totaldose was 50 Gy.

Figure 2 Disease course in case 1. *Transfusion of packedred blood cells separated from 400 mL of whole blood. APC,argon plasma coagulation.


Fantin et al.2 reported use of APC to treat hemor-rhagic radiation-induced proctosigmoiditis in 1999, andMorrow et al.3 reported a patient with radiation-induced carditis who was successfully treated with APCin 2000. Although many investigators have confirmedthe value of APC in treating many cases of radiation-induced proctosigmoiditis (Table 1),4–9 only twoinstances of APC therapy for radiation-induced gastritishave been reported.3,10 Although the distribution ofthese two patients’ gastritis differed from that of typicalradiation-induced gastritis after EBRT for bile ductcancer, APC ensured a better prognosis, as evident inour current cases.

Endoscopic clipping and injection therapy are inef-fective for arresting bleeding from a plane, althoughthey excel at stopping bleeding from a pinpoint. APC isespecially effective for arresting oozy bleeding from aplane, such as in the treatment of telangiectases ofvarious causes. In the current cases, APC was veryeffective in reducing the extent of telangiectasia andin decreasing or eliminating the need for a bloodtransfusion.

Because our observations are limited to two patients,further studies are necessary to confirm the effective-

ness of APC for this form of gastritis. If efficacy is estab-lished, safety of radiotherapy for biliary tract cancer willbe enhanced.

Shinichi Wada,Kiichi Tamada,

Takeshi Tomiyama,Hironori Yamamoto,

Katsuyuki Nakazawa,Kentaro Sugano

Department of Gastroenterology, Jichi Medical School,Tochigi, Japan

REFERENCES

1 Tamada K, Wada S, Ohashi A et al. Intraductal US inassessing the effects of radiation therapy and prediction ofpatency of metallic stents in extrahepatic bile duct carci-noma. Gastrointest. Endosc. 2000; 51: 405–11.

2 Fantin AC, Binek J, Suter WR, Meyenberger C. Argonplasma coagulation for treatment of symptomatic radia-tion-induced proctitis. Gastrointest. Endosc. 1999; 49:515–18.

3 Morrow JB, Dumot JA, Vargo JJ. Radiation-induced hem-orrhagic carditis treated with argon plasma coagulator.Gastrointest. Endosc. 2000; 51: 498–9.

4 Silva RA, Correia AJ, Dias LM, Viana HL, Viana RL.Argon plasma coagulation therapy for hemorrhagic radi-ation proctosigmoiditis. Gastrointest. Endosc. 1999; 50:221–4.

5 Tam W, Moore J, Schoeman M. Treatment of radiationproctitis with argon plasma coagulation. Endoscopy 2000;32: 667–72.

6 Kaassis M, Oberti E, Burtin P, Boyer J. Argon plasmacoagulation for the treatment of hemorrhagic radiationproctitis. Endoscopy 2000; 32: 673–6.

7 Tjandra JJ, Sengupta S. Argon plasma coagulation is aneffective treatment for refractory hemorrhagic radiationproctitis. Dis. Colon Rectum 2001; 44: 1759–64.

Table 1 Previously reported study of argon plasma coagulation (APC) therapy for radiation-induced proctitis and gastritis

Study group Location No. casesMean doseradiation

APC setting Required APC sessions

Power (W) Flow (L/min) Mean Median Range

Fantin et al. Proctitis 7 65 Gy 60 3.0 2.4 2 2–4Silva et al. Proctitis, sigmoiditis 28 NS 50 1.5 2.9 NS 1–8Tam et al. Proctitis 15 NS 60 2.0 NS 2.0 1–4Kaassis et al. Proctitis 16 NS 40 0.6 3.7 NS 2–8Tjandra et al. Proctitis 12 NS 40 1.5 2.0 2 1–3Taieb et al. Proctitis 11 NS 50 0.8–2.0 3.2 3 1–5Venkatesh et al. Proctitis 40 65–70 Gy 40–60 1.0–1.5 1.4 1 1–2Morrow et al. Carditis 1 60 Gy 50 2.0 – – 3Corbinais et al. Antritis, duodenitis 1 NS 55 0.6 – – 4Wada et al. Antritis 2 60 Gy 60 2.0 2.5 – 2,3

NS, not stated.

Figure 3 Disease course in case 2. *Transfusion of packedred blood cells separated from 400 mL of whole blood. APC,argon plasma coagulation.


8 Taieb S, Rolachon A, Cenni JC et al. Effective use of argonplasma coagulation in the treatment of severe radiationproctitis. Dis. Colon Rectum 2001; 44: 1766–71.

9 Venkatesh KS, Ramanujam P. Endoscopic therapy forradiation proctitis-induced hemorrhage in patients withprostatic carcinoma using argon plasma coagulator appli-cation. Surg. Endosc. 2002; 16: 707–10.

10 Corbinais S, Garin L, Pagenault M, Bretagne JF. Success-ful treatment by argon plasma coagulation of bleedingradiation-induced gastroduodenal vasculopathy. Endos-copy 2002; 34: 593.


PRIMARY LIVER SOMATOSTATINOMA

To the Editor,Neuroendocrine tumors are potentially malignant andoften metastasize to the liver. However, primary neu-roendocrine tumors arising in the liver are uncommonand the majority are carcinoid tumors.1 A huge hepaticneoplasm in a non-cirrhotic liver excised resembled awell-differentiated hepatocellular carcinoma (HCC)microscopically. Immunohistochemical studies, how-ever, identified the tumor as somatostainoma. An exten-sive postoperative search for a primary tumor includingultrasonography (US) of the abdomen, computedtomography (CT), magnetic resonance imaging (MRI)and [F18 ]fluoro-2-deoxy-D-glucose PET (FDG-PET)of the whole body did not identify another neuroendo-crine tumor. The tumor recurred in the remnant liverfive years after resection with the same histopathologyand immunostaining as the primary tumor. No soma-tostatinoma arising in the liver has been reported.

A 48-year-old woman was transferred to our hospitalbecause of a huge tumor in a non-cirrhotic liver. Shehad no endocrine symptoms of diabetes mellitus or ste-atorrhea, and had no neurofibromatosis. Laboratorydata showed normal liver function tests excluding lac-tate dehydrogenase 675 IU/L (< 400). Hepatitis B sur-face antigen (HBsAg) and antibodies to hepatitis Cvirus (HCV) were both negative. Serum alpha-fetopro-tein, carcinoembryonic antigen (CEA), and carbohy-drate antigen (CA19-9) levels were normal. A CT scandemonstrated a low-density mass approximately 20 cmin diameter with irregular contrast enhancement(Fig. 1a). The tumor had low signal intensity on T1-weighted imaging and increased signal intensity on T2-weighted imaging. A hepatic angiogram showed markedstretching of the tertiary braches and neovascularizationaround the periphery of the tumor without vascularencasement. The tumor was resected by an extendedright hepatectomy. Resected specimen showed a well-circumscribed tumor measuring 20 ¥ 20 ¥ 10 cm andweighing 3500 g, surrounded by a thin rim of fibrouscapsule. The cut surface showed predominantly abrown, round, well-circumscribed mass with a thincapsule (Fig. 1b). There was no necrosis or cysticformation. Microscopically, the tumor cells, small- tomedium-sized round cells with clear large cytoplasm,were predominantly arranged in a trabecular or ribbon

pattern separated by delicate fibrovascular stroma. Notubular or rosette formations were evident. The nucleiwere somewhat variable in size, round to ovoid, withdistinctive fine and stippled chromatin and some prom-inent nucleoli (Fig. 1c). Mitoses were not seen andthere was no evidence of necrosis or lymphovascularinvasion.

Immunohistochemical studies revealed that thetumor cells were positive for somatostatin (Fig. 1d),epithelial membrane antigen (EMA) and keratin, andwere stained to a lesser degree, with periodic acid-Schiff (PAS), Alican Blue, colloid Fe, and Grimeliusstains. The tumor cells did not react with mucicar-mine, neuron-specific enolase (NSE), insulin, gluca-gons, serotonin, gastrin, vasoactive intestinal peptide(VIP), adrenocorticotropic hormone (ACTH),chromogranin, a-fetoprotein, CEA, actin, Leu-7, ora-antitrypsin. Ultrastructurally, the tumor cells con-tained a single large vesicular nucleus with prominentnucleoli. Numerous, closely packed mitochondriawere seen in almost all tumor cells. Dense-core gran-ules ranging from 150 to 300 nm in diameter werepresent in a vast majority of the cells. Lipid dropletsand other organelles, such as rough endoplasmicreticulum, ribosomes and lysosomes, were sparse. Notonofilaments or cell junctions were observed. Thesomatostatin level in the tumor tissues was 18 ng/g,although serotonin, 5HTP and gastrin were notdetected. The tumor recurred in the remnant liver fiveyears after resection and was successfully resectedagain. Gross examination revealed a well-circum-scribed tumor measuring 11 ¥ 10 ¥ 10 cm and weigh-ing 520 g, surrounded by a thin fibrous capsule. Thesecond tumor had the same macroscopic, histologi-cal, ultrastructural, and immunohistochemical find-ings as the initial tumor.

The demonstration of somatostatin in tumor cells byimmunohistochemistry and the elevated level of tissuesomatostatin alone is strong evidence that the tumor inthe present case was a pure, somatostatin-producing,neuroendocrine tumor (somatostatinoma). Somatosta-tinomas of extra-hepatic origin have been reported andtheir metastases are seen most frequently in the liver.However, this tumor was unlikely to be of gastroentero-pancreatic (GEP) (or biliary) endocrine cell originbecause an extensive search failed to reveal a primarytumor in these organs, and it recurred in the liver fiveyears after resection.

Approximately 50 primary neuroendocrine neo-plasms of the liver have been reported,1 many ofwhich were mixed neuroendocrine tumors of GEPendocrine cells. Pure neuroendocrine tumors of theliver are rare, and pancreatic-polypeptide-producingor gastrin apudoma and VIPoma alone has beenreported.2,3 No somatostatinoma arising in the liverhas been reported previously. Endocrine cells withimmunoreactivity for serotonin, motilin, somatosta-tin, glucagon, gastrin and pancreatic polypeptide havebeen reported to be present in the intrahepatic biliarytree in the normal liver,4 and primary neuroendo-crine tumors are thought to arise from the intrahe-patic bile ducts. A primary hepatic neuroendocrinetumor surrounding the hepatic ducts might be pro-


found proof of this. Some neuroendocrine tumors areslow growing,5 and it is not known if the secondtumor in this case was a metastasis from the primarytumor or a new tumor. The absence of mitoses inthe tumor seems to indicate the latter.

Susumu Ohwada,*Takashi Joshita,†

Tsutomu Ishihara,†

Tetsunari Oyama,‡

Yoshikazu Inui,§

Junichi Aoki¶

Departments of *Surgery,†Laboratory Medicine and‡Tumor Pathology, Gunma University, Graduate School of

Medicine, ¶Diagnostic and Interventional Radiology,Gunma University Hospital, Maebashi and §Inui Clinic ofInternal Medicine, Shimokobana-machi, Takasaki, Japan

REFERENCES

1 Iwao M, Nakamuta M, Enjoji M et al. Primary hepaticcarcinoid tumor: case report and review of 53 cases. Med.Sci. Monit. 2001; 7: 746–50.

2 Warner TF, Seo IS, Madura JA, Polak JM, Pearse AG.Pancreatic-polypeptide-producing apudoma of the liver.Cancer 1980; 46: 1146–51.

3 Lundstedt C, Linjawi T, Amin T. Liver VIPoma: reportof two cases and literature review. Abdom. Imaging 1994;19: 433–7.

4 Kurumaya H, Ohta G. Endocrine cells in the intrahepaticbiliary tree in normal livers and hepatolithiasis. Arch.Pathol. Lab. Med. 1989; 113: 143–7.

5 Weynand B, Guiot Y, Doriaux M, Lefevre A, Fiasse R,Galant C. Motilin-producing liver and bone metastasesevidenced 14 years after resection of a rectal polyp. Am. J.Surg. Pathol. 1999; 23: 838–43.

Figure 1 (a) Computed tomography scan demonstrating a low-density mass approximately 20 cm in diameter with irregu-lar contrast enhancement. (b) Cut surface showing a predominantly brown, round, well-circumscribed mass, with a thin cap-sule. (c) Microscopically, the tumor cells, small- to medium-sized round cells with clear large cytoplasm, are predominantlyarranged in a trabecular or ribbon pattern separated by delicate fibrovascular stroma. No tubular or rosette formation wereseen. The nuclei are somewhat variable in size, round to ovoid, with distinctive fine, and stippled chromatin and some promi-nent nucleoli (HE ¥100). (d) Immunohistochemical microphotographs showing that the tumor cells are positive for soma-tostatin (¥200).

a b

c d



N-ACETYLCYSTEINE IN THE TREATMENT OF NON-ALCOHOLIC STEATOHEPATITIS

To the Editor,Non-alcoholic steatohepatitis (NASH) was oncethought to be a benign disease; however, data obtainedfrom some clinical series support the fact that the dis-ease might have a progressive clinical course which canculminate in liver cirrhosis.1 There is no general con-sensus on the effectiveness of any therapeutic agent inthe treatment of NASH.2

Factors such as oxidative stress and lipid peroxidationare important in the pathogenesis of NASH.3 Thismight make a wise basis for the use of antioxidants orother drugs that could protect hepatocytes from oxida-tive stress. N-acetylcysteine (NAC) is a glutathioneprecursor which increases glutathione levels in hepato-cytes.3 Increased glutathione levels, in turn, limit theproduction of reactive oxygen species which causehepatocellular injury.4 In the present study, the thera-peutic effect of NAC in the treatment of NASH wasinvestigated.

This study comprised 35 patients diagnosed withNASH based on liver biopsy and high alanine ami-notransferase (ALT) and/or aspartate aminotransferase(AST) levels on at least two occasions in the past 6months. Patients who had a > 30 g/day alcohol intakedetermined by a detailed personal history, interrogationof family members, and investigation of previous med-ical records, were excluded. Investigations into othercauses of liver disease included a hepatobiliary systemultrasound, viral serology, autoantibody titers, serumiron, ferritin and transferrin saturation, ceruloplasminand copper levels. Patients with steatohepatitis accom-panying other liver diseases, or systemic diseases otherthan obesity, hyperlipidemia, diabetes, intake of hepa-totoxic drugs or lipid-lowering agents were notincluded. The present study was approved by the Insti-tutional Review Board of the Cerrahpa a MedicalFaculty. All patients received detailed information

s

about the aim of the study and gave written, informedconsent to participate.

Patients were randomly divided into two groups: thefirst (18 patients) was administered NAC 600 mg/dayorally for 4 weeks, while the control group (17 patients)was followed up without therapy during this period. Atthe beginning of the study and at the end of the 4-weektreatment period, ALT, AST, gamma-glutamyl trans-ferase (GGT), alkaline phosphatase, bilirubin, albumin,globulin, glucose, cholesterol, triglycerides and bodymass index (BMI) were measured. Obesity was definedas a BMI > 29.5 kg/m2 for both sexes. Three patients inthe NAC group and two in the control group wereexcluded as they did not arrive on time for blood chem-istry tests. As a result, 15 patients in both groups wereable to complete the study. For statistical analysis, theMann–Whitney U-test and Wilcoxon test were used.

The NAC group consisted of 15 patients (8 male, 7female; mean age 49 ± 10). Obesity was present in two,hyperlipidemia in six; four patients had both obesityand hyperlipidemia, and one had both hyperlipidemiaand diabetes. The control group included 15 patients(10 male, 5 female; mean age 47.7 ± 9.5). In the controlgroup, one patient was obese, six hyperlipidemic, fiveboth obese and hyperlipidemic, and two were obese,diabetic and hyperlipidemic. All diabetic patients weretaking oral antidiabetic drugs.

Initially, there was no difference between the twogroups as far as age, BMI, ALT, AST, GGT and lipidprofiles were concerned (Table 1). At the end of the4-week period, both ALT and AST decreased in 12patients (80%), ALT becoming normal in three (20%)and AST in four patients (26.6%) in the NAC group. Inthe control group, ALT decreased in 11 patients(73.3%) and AST in six patients (40%). In this group,ALT levels normalized in five (33.3%) and AST levelsin two patients (13.3%). The decrease in ALT levels wassignificant in both groups; however, the decreases inAST and GGT levels were significant only in the NACgroup (Table 1) (P < 0.05). At the end of the 4 weeksthe changes in BMI, albumin, globulin, bilirubin, cho-

Table 1 Biochemical data and body mass index (BMI) in N-acetylcysteine (NAC) and control groups before and after the treat-ment periods

N-acetylcysteine Control

Initial After 4 weeks Initial After 4 weeks

ALT (U/L) 76.3 ± 24* 58.1 ± 25 74.9 ± 48† 59.9 ± 32AST (U/L) 47.3 ± 19* 37.3 ± 18 44.1 ± 15 39.5 ± 15GGT (U/L) 62.7 ± 50* 46.3 ± 25 51 ± 45 43.4 ± 37Triglyceride (mg/dL) 221.2 ± 89 224 ± 81 241.3 ± 116 228.8 ± 106Cholesterol (mg/dL) 216.1 ± 51 213 ± 46 223.6 ± 48 226.7 ± 56BMI (kg/m2) 27.1 ± 3 27.3 ± 3.8 29.1 ± 3 28.9 ± 3Total bilirubin (mg/dL) 0.9 ± 0.5 1.1 ± 0.6 1.0 ± 0.4 1.1 ± 0.4Albumin (g/dL) 4.92 ± 0.3 4.87 ± 0.3 4.74 ± 0.4 4.67 ± 0.5Globulin (g/dL) 3.01 ± 0.4 3.08 ± 0.5 2.92 ± 0.8 2.88 ± 0.7

Values are given as mean ± standard deviation.* P < 0.05, initially and after 4 weeks in the NAC group; † P < 0.05, initially andafter 4 weeks in the control group.


lesterol and triglycerides were not significant in eithergroup.

In our study the significant decrements in ALT, ASTand GGT levels following a 4-week treatment periodwith NAC might be interpreted to be a result of thetherapeutic effect of NAC. However, when data con-cerning the control group is considered it is apparentthat ALT levels decreased, as seen in the treatmentgroup, and this casts some doubt on the therapeuticvalue of NAC. We can suggest that factors which mightaffect the course of NASH and have changed similarlyin both groups have been determinative. The first prob-ability is that these factors act together with the meta-bolic disorders accompanying NASH. However, in boththe NAC and control groups, BMI and lipid profiles didnot change significantly; our major aim when planninga treatment period as short as 4 weeks was to keep theeffects of variables including weight loss and lipid pro-files at a minimum, even negligible level. Also, anotherreason which might explain the results of our study isthe fluctuations in ALT and AST levels which naturallyoccur during the course of the disease.

Until now, there has only been one study which usedNAC for the treatment of NASH.5 In this uncontrolledstudy, NAC (1 g/day) was administered to 11 NASHpatients for 3 months, with significant improvements inaminotransferase levels. Experimental studies showedthat the daily amount of glutathione synthesis inhumans is 10–15 g and most of the sources of this areprovided from the natural sources of the organism.Therefore, it is difficult to state that an amount of600 mg given exogenously affects glutathione synthesisto a great extent.

In the present study, improvements in biochemicalparameters in patients with NASH was not interpretedas the therapeutic effect of the drug. The more fluctu-ating course of the biochemical parameters in NASH,as compared to viral hepatitis, makes the evaluation ofdata much more difficult. It is an obligation to developmore confidential criteria to interpret the results of ther-apy, while we search for more effective treatment strat-egies for a disease whose natural course remains largelyunknown.

Gülsüm Emel Pamuk,Abdullah Sonsuz

Division of Hepatology, Department of Internal Medicine,Cerrahpapa Medical Faculty, University of Istanbul,

Istanbul, Turkey

REFERENCES

1 Teli MR, James OFW, Burt AD, Bennett MK, Day CP.The natural history of nonalcoholic fatty liver: a follow-upstudy. Hepatology 1995; 22: 1714–19.

2 Angulo P, Lindor KD. Treatment of nonalcoholic fattyliver: Present and emerging therapies. Sem. Liver Dis.2001; 21: 81–8.

3 Letteron P, Fromenty B, Terris B, Degott C, Pessayre D.Acute and chronic hepatic steatosis leads to in vivo lipidperoxidation in mice. J. Hepatol. 1996; 24: 200–8.


GENETIC HEMOCHROMATOSISWITH NORMAL TRANSFERRINSATURATION IN A MAN WITH CHOLANGIOCARCINOMA ANDYELLOW NAIL SYNDROME

To the Editor,We report a case of hereditary hemochromatosis withnormal transferrin saturation in a 54-year-old male withcholangiocarcinoma. The patient was referred for severeweight loss. His medical history was unremarkable andchronic alcoholism was excluded. Medical examinationshowed nails of a pale yellow color, extremely hard,slightly thicker and excessively curved on their long axis(Fig. 1a). Erythrocyte sedimentation rate (ESR), bloodcount, liver enzymes, bilirubin, coagulation screen, albu-minemia, immunoglobulins, glucose metabolism, crea-tinine, urine tests, plasma electrolytes and thyroidfunction tests were normal. Screening for the hepatitis Band C virus were negative and a chest radiograph wasnormal. Abdominal ultrasound showed a 3 cm diameterhypo-echoic area in the VIII hepatic segment, close to theinferior vena cava. A computed tomography (CT) scanconfirmed the presence of a hypodense nodule in theliver of increased density; the nodule maintained the lowattenuation value on enhancement. An upper gas-trointestinal endoscopy and colonoscopy showed noabnormalities. Air contrast barium enema of the smallbowel was normal. Magnetic resonance imaging (MRI)revealed the nodule to be hypointense with a peripheralwedge-like enhancement area, and there was a dramaticdecrease in liver signal intensity due to iron overload,leading to a high contrast with the nodule itself (Fig. 1b).

Laboratory testing for iron metabolism found serumiron 27 mmol/L (12–30 mmol/L), transferrin saturation43% (25–45%), transferrin 2.9 g/L (2–4 g/L) andserum ferritin 3300 mg/L (20–300 mg/L). After an endo-scopic retrograde cholangiography and arteriography,the patient underwent a trisegmentectomy. Histologyshowed a massive iron overload in a non-cirrhotic butfibrotic liver and a well-differentiated cholangiocarci-noma devoid of iron (Fig. 1c). Immunohistochemistryof the cholangiocarcinoma demonstrated strong expres-sion of cytokeratins CK7 and CK20 (Dako, CA, USA)(Fig. 1d). Genotype analysis (polymerase chain reac-tion amplification and digestion with restriction enzymeRsaI) confirmed the presence of hereditary hemochro-matosis (C282Y homozygosity and absence of H63Dmutation of the HFE gene), despite the atypical bio-chemistry.

The patient received 4-monthly cycles of 5-fluorouracil and levamisole postoperatively. After sur-

4 Pastor A, Collado PS, Almar M, Gonzalez-Gallego J.Antioxidant enzyme status in biliary obstructed rats:effects of N-acetylcysteine. J. Hepatol. 1997; 27: 363–70.

5 Gülbahar O, Karasu ZA, Ersöz G et al. Treatment non-alcoholic steatohepatitis with N-acetylcysteine (Abstract).Gastroenterology 2000; 118: A1444.


gery there was a quick improvement in his dystrophicyellow nails, which appeared normal by the end of thechemotherapeutic regimen. Six months after the lastcycle of chemotherapy, the patient was started onweekly, followed by quarterly, therapeutic phlebotomy.

The earliest biochemical abnormality observed inhereditary hemochromatosis is an elevation in serumtransferrin saturation, which represents the transport ofexcess iron from the intestine and occurs before signif-icant iron loading.1 As iron accumulates in tissue, theserum ferritin concentration increases in a linear rela-tionship with total body iron stores. The present patientrepresents a case of primary hepatic iron overload withhyperferritinaemia and normal transferrin.2 However,previously reported cases differ from ours as they hadmuch lower serum ferritin levels and the majority exhib-ited features of ‘insulin resistance syndrome’. Transfer-rin saturation is usually a very reliable indicator of ironoverload disorders, while serum ferritin is often unreli-able, especially in the early and preclinical phase. How-ever, transferrin saturation may not be elevated,requiring other methods such as MRI and liver histol-ogy for confirmation of iron overload. This deficit inbiochemical measurements in the diagnosis of ironoverload highlights the usefulness of genotype analysis.3

Our patient had cholangiocarcinoma, which presum-ably induced a paraneoplastic syndrome with charac-teristic nail changes. The yellow nails completelyreverted to normal after treatment, which was alsoobserved in another patient after successful treatmentof breast cancer.4

Various malignancies have been associated with yel-low nail syndrome. Possible pathogenesis of this syn-drome includes direct involvement of cancer in alreadydefective lymphatic drainage, or the release of media-tors such as peptide hormones which impair lymphaticfunction. Thus, yellow nails might be a paraneoplasticsyndrome that could be resolved after effective cancertreatment.4

The current case raises the possibility that the cho-langiocarcinoma was related to iron overload, as otherknown carcinogenetic factors were not present. Cho-langiocarcinoma is rarely associated with hemochro-matosis, however, iron overload may contribute to therare development of hepatocellular carcinoma in non-cirrhotic livers.5 Primary carcinomas developing inhemochromatotic livers are always devoid of iron.MRI might allow the detection of iron-free nodules inhemochromatotic livers and could be extremely use-ful for identifying early lesions strongly suspected ofbeing neoplastic.

Fabio Di Stefano,Nicola Verna,

Loukia Balatsinou,Cosima Schiavone,

Mario Di GioacchinoDepartment of Medicine and Science of Aging, University of

Chieti, Pescara, Italy

REFERENCES

1 Whittington CA, Kowdley KV. Haemochromatosis. Ali-ment Pharmacol. Ther. 2002; 16: 1963–75.

2 Moirand R, Mortaji AM, Loreal O, Paillard F, Brissot P,Deugnier Y. A new syndrome of liver iron overload withnormal transferrin saturation. Lancet 1997; 349: 95–7.

3 Rossi E, Henderson S, Chin CY et al. Genotyping as adiagnostic aid in genetic haemochromatosis. J. Gastroen-terol. Hepatol. 1999; 14: 427–30.

4 Iqbal M, Rossoff LJ, Marzouk KA, Steinberg HN. Yellownail syndrome: resolution of yellow nails after successfultreatment of breast cancer. Chest 2000; 117: 1516–18.

5 Deugnier YM, Guyader D, Crantock L et al. Primary livercancer in genetic haemochromatosis: a clinical, patholog-ical and pathogenetic study of 54 cases. Gastroenterology1993; 104: 228–34.

Figure 1 (a) Atypical nailsappearance. (b) Magnetic res-onance image with T1 andT2 weighted gradient echosequences. The hypointensenodule between segmentsVIII and IV is well-defined inan iron overloaded liver char-acterized by a dramatic fall insignal intensity. (c) Junctionbetween the cholangiocarci-noma (bottom left) com-pletely devoid of iron and thenon-tumorous hepatic tissue(top right) with Perls stainingstrongly positive. (d) Immu-nohistochemistry of the cho-langiocarcinoma stronglyexpressing cytokeratins CK7and CK20 (Dako, CA, USA).



FAT DROPLETS AROUND THELIVER AND SPLEEN

To the Editor,The present case report investigated fat droplets aroundthe liver and spleen evident on a computed tomography(CT) scan of an 89-year-old woman who developedacute renal failure. Although the origin of the fat wasunclear, her lumbar muscles were necrotic. Release offat from lumbar muscles with fatty changes caused byrhabdomyolysis was one of the possible sources of fatdroplets which migrated cranially within the abdominalcavity. The conversion of fatty acids into fat dropletsrequires compartmentation for transport, but no infor-mation is available in published works regarding this.Fat droplets around the liver have never been reportedbefore.

An 89-year-old woman entered San-ai MemorialHospital on April 30 2002 because of hypertension, hia-tus hernia, anemia and hypoalbuminemia. On admis-sion, she complained of severe prostration, malaise,headache and lumbago, and her blood pressure was166/74 mmHg. Laboratory tests included: white bloodcell (WBC) 7200/mL, red blood cell (RBC) 195 ¥ 104/mL, hemoglobin 6.6 g/dL, hematocrit 19.8%, platelet21.5 ¥ 104/mL, blood sugar 147 mg/dL, total protein5.9 g/dL, albumin 2.7 g/dL, gamma-globulin 25.3%,zinc sulfate turbidity (ZTT) 12.9, erythrocyte sedimen-tation rate 129 mm/L h and 240 mm/2 h, creatinine1.18 mg/dL, blood urea nitrogen (BUN) 18.2 mg/dL,sodium 132.0 mmol/L, potassium 6.0 mmol/L, chlo-ride 102.0 mmol/L, C-reactive protein 7.3, HBsAg andhepatitis C virus antibodies (–). Serum myeloperoxi-dase-antineutrophil cytoplasmatic antibodies (MPO-ANCA) were above 640 U/mL.1

Following this the patient developed muscle crampsin the face and upper extremities. Her serum creatininerose to 4.7 mg/dL and BUN to 53.4 mg/dL on April 30,and kept rising. On May 3, with a creatinine reading of5.5 mg/dL, she was transferred to our hospital with atentative diagnosis of acute progressive glomerulone-phritis and hemodialysis commenced that day. Musclecramps frequently occurred in the upper extremities.Her general condition progressively deteriorated andshe died on July 16 2002.

The most conspicuous finding was accumulation offat droplets between the surface of the liver and spleenand the peritoneum (Fig. 1). These droplets usuallyreside within the peritoneal cavity, not in the retroperi-toneum. That they are different from air is obvious fromthe irregularity of the boundary between the very lowattenuating area and the organ. The lumbar muscleswere very low at the CT level, suggesting necrosis. Forcomparison, we observed normal lumbar muscles at asimilar level of the lower kidney pole. It is known thatthese muscles undergo fatty changes as age advances,and elderly people have increased amounts of fat intheir muscles.

Rabdomyolysis of lumbar muscles in the presentpatient was a possible source of fatty acids. It wasassumed that rabdomyolysis had additive effects on thedevelopment of acute renal failure besides MPO-

ANKA.2,3 Released fatty acids from lumbar musclespermeate through the peritoneum because of their smallmolecular size. Fatty acids that have entered the pelvicperitoneal cavity will form fatty acid fluid that has to betransported for exclusion. Other sources of fatty acidswithin the abdominal cavity cannot be ruled out, butthere have been no such reports.

Fatty acid fluid cannot move unless it is compart-mented. For compartmentation, fatty acids have toacquire some protein, lipoprotein and fatty acids fromthe peritoneal fluid to be encompassed within theformed capsules. We assume this is what occurred in thepresent case. After formation of fat droplets they aretransported cranially, due perhaps to specific gravity ofthe droplets and the suction effect of the diaphragm.The diaphragm is known to have a suction effect andtransports lymph and ascites into the thorax.4,5 These fatdroplets were most likely transported into the left sub-clavian vein as in the thoracic duct lymph.

Kunio Okuda,*Susumu Kobayashi,†

Kazuaki Nakajima,‡

Yoshio Ohtake,‡

Yasubumi Irie‡

*Departments of Medicine and Clinical Oncology and†Academic Surgery, Graduate School of Medicine, Chiba

University, and ‡San-ai Memorial Hospital, Chiba, Japan

REFERENCES

1 Anders HJ, Wiebecke B, Haedecke C, Sanden C, CombeC, Schlondorff D. NPO-ANCA-Positive crescentic glom-erulonephritis. a distinct entity of scleroderma renal dis-ease? Am. J. Kidney Dis. 1999; 33: 1–3.

2 Kusus M, Stapleton DD, Lertora JJ, Simon EE,Dreisbach AW. Rhabdomyolysis and acute renal failurein a cardiac transplant recipient due to multiple druginteractions. Am. J. Med. Sci. 2000; 320: 394–7.

Figure 1 Accumulation of fat droplets around the liver andin the area cranial to the spleen (arrows). The boundariesbetween the fat and the liver are irregular unlike water, andcontain round bubble-like structures (small arrows).


3 Mogyorosi A, Bradley B, Showalter A, Schubert ML.Rhabdomyolysis and acute renal failure due to combina-tion therapy with simvastatin and warfarin. J. Intern. Med.1999; 246: 599–602.

4 Fritz DL, Waag DM. Transdiaphragmatic lymphatictransport of intraperitoneally administered marker inhamsters. Lab. Anim. Sci. 1999; 49: 522–9.

5 Zakaria ER, Simonsen O, Rippe A, Rippe B. Transport oftracer albumin from peritoneum to plasma: role of dia-phragmatic, visceral, and parietal lymphatics. Am. J. Phys-iol. 1996; 270: H1549–56.

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