Clin J Gastroenterol (2009) 2:310–314 DOI 10.1007/s12328-009-0087-7

CASE REPORT

Autopsy case of acute liver failure due to scrub typhus Yoshihiro Shioi Æ Akihiko Murakami Æ Yasuhiro Takikawa Æ Yoshiharu Miyate Æ Nobukazu Tomichi Æ Kazuo Takayama Æ Noriyuki Uesugi Æ Tamotsu Sugai

Received: 2 February 2009 / Accepted: 5 April 2009 / Published online: 28 May 2009 Ó Springer 2009

Abstract Scrub typhus (Tsutsugamushi disease) is an acute febrile disease caused by infection with Orientia tsutsugamushi transmitted by mites. Although patients with scrub typhus commonly display mild liver injury, few die of acute liver failure. We describe herein an autopsy case of acute liver failure due to scrub typhus, which was complicated by disseminated intravascular coagulation and showed rapid progression of liver injury just before death. Histopathological findings revealed submassive hepatocellular necrosis, inflammatory cell infiltration in Glisson’s capsules, and sporadic fibrin thrombi in the hepatic sinusoids. Cause of death was primarily associated with acute liver failure related to disseminated intravascular coagulation.

Keywords Scrub typhus (Tsutsugamushi disease)  Acute liver failure  Massive hepatic necrosis  Disseminated intravascular coagulation (DIC)

Y. Shioi (&)  N. Uesugi  T. Sugai Division of Molecular Diagnostic Pathology, Department of Pathology, School of Medicine, Iwate Medical University, 19-1 Uchimaru, Morioka 020-8505, Japan e-mail: [email protected]

Y. Miyate Department of Intensive Care Unit, Iwate Prefectural Central Hospital, 1-4-1 Ueda, Morioka 020-0066, Japan e-mail: [email protected]

N. Uesugi e-mail: [email protected] T. Sugai e-mail: [email protected] A. Murakami Department of Endoscopy, Iwate Prefectural Central Hospital, 1-4-1 Ueda, Morioka 020-0066, Japan e-mail: [email protected] Y. Takikawa Department of Gastroenterology and Hepatology, School of Medicine, Iwate Medical University, 19-1 Uchimaru, Morioka 020-8505, Japan e-mail: [email protected]

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Introduction Scrub typhus invites various complications of clinically varying severity [1–4]. Although hepatic injury is well known to be frequently associated with the course of scrub typhus [5–7], few cases progressing to fatal acute liver failure have been reported in the English-language literature [8]. We report herein an autopsied case of scrub typhus associated with acute liver failure based on submassive hepatocellular necrosis histologically.

N. Tomichi  K. Takayama Department of Pathology, Iwate Prefectural Central Hospital, 1-4-1 Ueda, Morioka 020-0066, Japan N. Tomichi e-mail: [email protected] K. Takayama e-mail: [email protected]

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Case report A 73-year-old woman engaged in farm work visited a clinic on 10 May 2002, with a 3-day history of high fever, rash, headache, and malaise. Blood testing showed white cell count 8,900/ll and C-reactive protein 6 mg/dl. Combined glycyrrhizin glycine cysteine was administered and an antiallergic agent (cetirizine hydrochloride) was prescribed for rash. On 12 May 2002, she was admitted to the clinic with persistent high fever and rash, and development of anorexia. Intravenous drip infusion of antibiotics (fosfomycin sodium) was initiated, based on a diagnosis of bacterial infection. However, jaundice was noted the following day, and biochemical testing showed liver injury. On 14 May 2002, she was transferred to our general hospital for further examination due to persistent high fever, jaundice, and liver injury. At time of admission, she was disoriented and vital signs were blood pressure 93/47 mmHg, heart rate 94 beats/min, and body temperature 38.4°C. Black eschar was apparent on the pubic mound and macular erythematous rash was seen over the trunk. The superficial lymph nodes were not palpable. Laboratory findings on 14 May 2002 are shown in Table 1. White cell count was 15,340/ll, hemoglobin count was 11.3 g/dl, and platelet count was 35 9 103/ll. Aspartate aminotransferase (AST) level was 198 IU/L (normal \40 IU/l), alanine aminotransferase (ALT) level was 54 IU/L (normal\35 IU/l), and total bilirubin (T-Bil) level was 1.75 mg/dl (normal \1.1 mg/dl). C-reactive protein

level was 28.16 mg/dl. Prothrombin time activity was 50% (normal 70–130%), and fibrinogen degradation product (FDP) level was 46 lg/ml (normal \10 lg/ml). Negative results were obtained for both hepatitis B virus surface antigen and hepatitis C virus antibody. Elevated AST, ALT, and T-Bil levels were consistent with mild liver injury, and the decreased prothrombin time activity and coagulation abnormality were attributed to disseminated intravascular coagulation (DIC). Blood gas analysis showed hypoxia and respiratory alkalosis. Electrocardiography showed no abnormalities. Chest radiography showed reticular shadows in bilateral lower lobes. Chest computed tomography (CT) showed ground-glass opacities in bilateral lower lobes and slight pleural effusion. Abdominal CT showed hepatomegaly, splenomegaly, and a gallstone without wall thickening or enlargement of the gallbladder. Clinical diagnosis was scrub typhus, based on the typical eschar, fever, and rash, and she was admitted to the intensive care unit for treatment of the complications of respiratory failure and DIC. The clinical course is outlined in Fig. 1. She was administered minocycline hydrochloride at 200 mg/day for scrub typhus and mechanical ventilation therapy for respiratory failure. Gabexate mesilate (a synthetic serine–protease inhibitor compound), fresh frozen plasma, and platelet substitution therapy were also used for the DIC. Despite these intensive therapies, body temperature remained[38°C and gastrointestinal bleeding developed. Consequently, anticoagulation therapy was suspended and a blood

Table 1 Laboratory data on admission (14 May 2002, day 8) Complete blood count

Blood biochemistry 3

Arterial blood gas analysis

WBC

15.34 9 10 /ll

T-Bil

1.75 mg/dl

pH

7.501

RBC

3.86 9 106/ll

AST

198 IU/l

PaCO2

26 mmHg

Hb

11.3 g/dl

ALT

54 IU/l

PaO2

67 mmHg

Ht

32.20%

LDH

1,014 IU/l

HCO3-

20.1 mmol/l

Plt

35 9 103/ll

ALP

313 IU/l

Base excess

-1.1 mmol/l

c-GTP

43 IU/l

SpO2

95% (O2 5 L/min)

Coagulation test PTA

50%

AMY

219 IU/l

Urinalysis

APTT

59.5 s

CPK

428 IU/l

Color

Yellow

Fibrinogen

114 mg/dl

BUN

62.9 mg/dl

Protein

1?

FDP

46 lg/dl

Cr

1.2 mg/dl

Sugar



ATIII

32%

Na

138.2 mEq/l

Occult blood

2?

K

4.2 mEq/l

Bilirubin



Viral markers HBs Ag

(–)

Cl

104.8 mEq/l

Acetone body



HCV Ab

(–)

TP CRP

4.6 g/dl 28.16 mg/dl

Leukocytes



WBC white blood cells, RBC red blood cells, Hb hemoglobin, Ht hematocrit, Plt platelets, PTA prothrombin time activity, APTT activated partial thromboplastin time, FDP fibrinogen degradation products, ATIII anti-thrombin III, HBs Ag hepatitis B surface antigen, HCV Ab hepatitis C virus antibody, T-Bil total bilirubin, AST aspartate aminotransferase, ALT alanine aminotransferase, LDH lactate dehydrogenase, c-GTP c-glutamyl transpeptidase, BUN blood urea nitrogen, Cr creatinine

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Clin J Gastroenterol (2009) 2:310–314

antibody testing for Orientia tsutsugamushi (Ot) on admission showed immunoglobulin (Ig)M titers of 1:\20 to the Kato strain, 1:20 to the Karp strain, and 1:20 to the Gillium strain, and IgG titers of 1:80 to the Kato strain, 1:[640 to the Karp strain, and 1:320 to the Gillium strain. These serological results confirmed the diagnosis of Karp-type scrub typhus according to the criteria of the National Institute of Infectious Diseases in Japan. Polymerase chain reaction showed negative results for Ot based on examinations of serum, liver tissue, and spleen tissue. Autopsy results

Fig. 1 Clinical course of a 73-year-old female patient admitted to our hospital with fever and rash. Scrub typhus was diagnosed and treatment was initiated with minocycline hydrochloride (MINO), mechanical ventilation (MV), and continuous hemodiafiltration (CHDF). Laboratory findings showed marked elevation of AST and ALT levels, decreased prothrombin activity, and increased total bilirubin levels. She died on day 11 of the illness. AST aspartate aminotransferase, ALT alanine aminotransferase, PTA prothrombin time activity, T-Bil total bilirubin, BUN blood urea nitrogen Table 2 Clinical data for renal function Days from onset

8

BUN (mg/dl)

62.9

Cr (mg/dl)

9

1.2

64.2 1.71

10

11

59.7

30.4

2.18

Autopsy was performed 4 h after death. Black eschar was observed on the pubis, and edema and icterus were evident over the entire body. Hemorrhagic ascites (300 ml) was present in the peritoneal cavity. Macroscopically, the liver (1,450 g) was jaundiced and congested. Microscopically, submassive hepatocellular necrosis and fatty degeneration was seen in surviving and degenerated hepatocytes. Marked infiltration of macrophages, lymphocytes, and plasma cells was seen in Glisson’s capsules, and increased numbers of Kupffer cells and inflammatory cells were present in the sinusoids. Sporadic fibrin thrombi were apparent in the hepatic sinusoids (Fig. 2). Gross examination showed left ventricular hypertrophy of the heart (420 g), congestion, edema, and focal bleeding in the lungs (left, 630 g; right, 640 g), and edema and petechial hemorrhage in the renal pelvis of the kidneys (left, 200 g; right, 180 g). Splenomegaly (220 g) was observed with congestion and focal necrosis. Mesenteric lymph nodes were slightly swollen. The gastrointestinal tract showed diffuse erosion and bleeding. Microscopically, inflammatory cell infiltration of lymphocytes, plasma cells, and macrophages in the interstitium were observed in lungs, heart, kidneys, and adrenal glands, and particularly in the liver, spleen, and mesenteric lymph nodes. Proliferation of macrophages was evident, particularly in the liver, spleen, and mesenteric lymph nodes. Erythrophagocytosis was observed in the liver and spleen.

1.69

BUN blood urea nitrogen, Cr creatinine

Discussion

transfusion was provided. The following day she became oliguric, and was treated with continuous hemodiafiltration under a diagnosis of acute renal failure. The results of renal function tests are shown in Table 2. In addition, hepatic injury deteriorated rapidly, and serum AST and ALT levels were markedly elevated at 2 days prior to death, reaching 24,100 and 5,183 IU/ml, respectively. The patient died on 17 May 2002, on day 11 of the illness (day 4 of hospitalization). On this last day, blood ammonia level was 285 lg/dl (normal B75 lg/dl). Indirect immunofluorescent

Scrub typhus (Tsutsugamushi disease) is an acute febrile disease caused by infection with Ot transmitted by the bite of host mites [9]. The disease is endemic over a wide area of the Asia–Pacific region. With the increasing incidence of the disease in Japan over the last three decades, scrub typhus has been recognized as an imported infectious disease and a re-emerging infectious disease. The major clinical symptoms such as fever, rash, and characteristic eschar are key to clinical diagnosis of the disease [5]. The mainstay of scrub typhus diagnosis is serologic testing [10].

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Fig. 2 Histological images of the liver specimen at autopsy. a Submassive hepatocellular necrosis in the center and middle zone of the hepatic lobule. Fatty degeneration in surviving and degenerated hepatocytes in the peripheral zone of the lobule. Marked infiltration of macrophages, lymphocytes, and plasma cells in Glisson’s sheath.

Swelling of endothelial cells in the vein and bile cast in the bile duct were observed in Glisson’s sheath [hematoxylin and eosin (H&E) staining, 9100]. CV central vein. b A fibrin thrombus (arrow) in the hepatic sinusoids (phosphotungstic acid hematoxylin staining, 9400)

Target cells for Ot are endothelial cells and macrophages [11, 12], with the organism disseminating into multiple organs through endothelial cells and predominantly locating in macrophages of the liver and spleen [11]. The bacteria then causes systemic vasculitis and perivasculitis in multiple organs, with various complications. The main serious complications of scrub typhus are circulatory failure, respiratory failure, and cerebral involvement [3, 4]. DIC is also a life-threatening state, and the morbidity rate is 14% in patients with scrub typhus [5]. Hepatic injury is common in the surveillance of scrub typhus. Elevated levels of AST and ALT are detected in 74.5–89.3% and 74.5–91.7% of patients, respectively, but serious liver involvement is rarely reported [5–7]. Although some pathological liver findings of scrub typhus in surviving patients have been reported, such as nonspecific reactive hepatitis and granulomatous hepatitis [13, 14], acute liver failure with histological findings has been rarely reported [2–4, 8]. Most reports of pathological liver findings from autopsy cases of scrub typhus were reported during World War II, comprising: (1) increased sinusoidal cells such as swollen Kupffer cells, lymphocytes, plasma cells, and basophilic macrophages; (2) phagocytosis by swollen Kupffer cells; (3) infiltration of mononuclear cells in periportal areas; (4) fatty degeneration, principally in periportal areas; and (5) focal necrosis [2–4]. Even focal necrosis has been reported in only 9–25% of autopsy cases [2, 3]. The present case is thus a rare example of scrub typhus resulting in death from acute liver failure based on submassive hepatocellular necrosis. The patient was clearly affected by DIC, which induced multiple organ failure, involving respiratory failure, renal failure, gastrointestinal bleeding, and hepatic failure. Above all, hepatic failure appears to have been the most

final critical factor, as supported by the marked elevation in liver enzyme levels and the submassive hepatic necrosis. Two hypotheses can be proposed to explain the mechanism by which Ot infection causes submassive hepatocellular necrosis. First, as a result of DIC, microcirculatory disturbance caused by sinusoidal microthrombi might invite hepatocellular necrosis. In the present case, DIC had already occurred on admission, and rapid increases in transaminase levels were observed just before death. Scattered microthrombi in the sinusoids revealed by the histological examination might thus have invited submassive hepatocellular necrosis by microcirculatory disturbance. Second, direct injury to the endothelial cells by Ot might invite microcirculatory disturbances leading to submassive hepatocellular necrosis. As Ot can be detected within endothelial cells in any organs and in macrophages located in the liver and spleen [11, 12], Ot might directly damage the hepatic microvasculature, leading to submassive hepatocellular necrosis. As both DIC and Ot injure the reticuloendothelial system, both hypotheses are plausible. The former hypothesis is particularly important to illuminate the process of acute liver failure. This process has been confirmed in animal experiments [15], but has rarely been identified in clinical situations, since confirmation of fibrin thrombi at the time of completed massive hepatocellular necrosis is difficult. In this autopsy case, surviving hepatocytes were surrounded by submassive hepatic necrosis. This might be a critical moment morphologically capturing the occurrence of massive hepatic necrosis induced by sinusoidal microthrombi. In most cases of scrub typhus, antimicrobial therapy such as tetracycline and chloramphenicol appears effective. Serious complications of scrub typhus generally occur in the second week of untreated illness [3]. Precise diagnosis

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and early appropriate antibiotic treatment can thus avoid life-threatening complications. In conclusion, we have reported an autopsy case of scrub typhus with submassive hepatic necrosis and sporadic fibrin thrombi in the hepatic sinusoids on histological examination. The main cause of death was associated with acute hepatic failure related to DIC. Acknowledgments The authors wish to thank Shin-ichi Nakamura (supervisor, DPR, Morioka, Japan; former Professor of Pathology at Iwate Medical University) for contributing to the pathological investigations.

References 1. Tsay RW, Chang FY. Serious complications in scrub typhus. J Microbiol Immunol Infect. 1998;31:240–4. 2. Allen AC, Spitz S. A comparative study of the pathology of scrub typhus (tsutsugamushi disease) and other rickettsial diseases. Am J Pathol. 1945;21:603–81. 3. Settle EB, Pinkerton H, Corbett AJ. A pathologic study of tsutsugamushi disease (scrub typhus) with notes on clinicopathologic correlation. J Lab Clin Med. 1945;30:639–61. 4. Levine DH. Pathologic study of thirty-one cases of scrub typhus fever with especial reference to the cardiovascular system. Am Heart J. 1946;31:314–28. 5. Ogawa M, Hagiwara T, Kishimoto T, Shiga S, Yoshida Y, Furuya Y, et al. Scrub typhus in Japan: epidemiology and clinical features of cases reported in 1998. Am J Trop Med Hyg. 2002;67:162–5.

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Clin J Gastroenterol (2009) 2:310–314 6. Yang CH, Hsu GJ, Peng MY, Young TG. Hepatic dysfunction in scrub typhus. J Formos Med Assoc. 1995;94:101–5. 7. Hu ML, Liu JW, Wu KL, Lu SN, Chiou SS, Kuo CH, et al. Short report: abnormal liver function in scrub typhus. Am J Trop Med Hyg. 2005;73:667–8. 8. Deepak NA, Patel ND. Differential diagnosis of acute liver failure in India. Ann Hepatol. 2006;5:150–6. 9. Tamura A, Ohashi N, Urakami H, Miyamura S. Classification of Rickettsia tsutsugamushi in a new genus, Orientia gen. nov., as Orientia tsutsugamushi comb. nov. Int J Syst Bacteriol. 1995; 45:589–91. 10. Blacksell SD, Bryant NJ, Paris DH, Doust JA, Sakoda Y, Day NP. Scrub typhus serologic testing with the indirect immunofluorescence method as a diagnostic gold standard: a lack of consensus leads to a lot of confusion. Clin Infect Dis. 2007; 44:391–401. 11. Moron CG, Popov VL, Feng HM, Wear D, Walker DH. Identification of the target cells of Orientia tsutsugamushi in human cases of scrub typhus. Mod Pathol. 2001;14:752–9. 12. Tseng BY, Yang HH, Liou JH, Chen LK, Hsu YH. Immunohistochemical study of scrub typhus: a report of two cases. Kaohsiung J Med Sci. 2008;24:92–8. 13. Kanno A, Yamada M, Murakami K, Torinuki W. Liver involvement in tsutsugamushi disease. Tohoku J Exp Med. 1996; 179:213–7. 14. Chien RN, Liu NJ, Lin PY, Liaw YF. Granulomatous hepatitis associated with scrub typhus. J Gastroenterol Hepatol. 1995; 10:484–7. 15. Mochida S, Arai M, Ohno A, Yamanobe F, Ishikawa K, Matsui A, et al. Deranged blood coagulation equilibrium as a factor of massive liver necrosis following endotoxin administration in partially hepatectomized rats. Hepatology. 1999;29:1532–40.

Autopsy case of acute liver failure due to scrub typhus.

Scrub typhus (Tsutsugamushi disease) is an acute febrile disease caused by infection with Orientia tsutsugamushi transmitted by mites. Although patien...
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