Liver manifestations of tick-borne diseases.

Abstract

INTRODUCTION In the US, the most common zoonotic infections are tick-borne diseases with clinical presentations ranging from asymptomatic to fulminant life-threatening infections. Ticks are a reservoir for bacterial, viral, and parasitic organisms and are responsible for a myriad of disease entities including but not limited to Lyme disease, babesiosis, ehrlichiosis, anaplasmosis, Rocky Mountain spotted fever (RMSF), tick-borne relapsing fever (TBRF), tularemia, Colorado tick fever, and Q fever (Table 1). This review focuses on the characteristic hepatological manifestations and pathogenetic mechanisms associated with tick-borne diseases to aid physicians with the challenging diagnostic pathway and associated preventable sequalae of these diseases. Table 1 - Geographical distribution and patterns of liver injuries of tick-borne diseases in North America Disease Geographical distribution Infectious agent Seasonality Pattern of liver injury Recommended treatmenta Lyme disease Northeastern and Midwestern states Borrelia burgdorferi Summer–Autumn Hepatocellular Doxycycline or amoxicillin or cefuroxime RMSF Eastern states 60% of cases reported in North Carolina, Oklahoma, Arkansas, Tennessee, and Missouri Rickettsia rickettsii Spring–Summer Cholestatic Doxycycline Human monocytic ehrlichiosis South-Central, South-Atlantic, and Mid-Atlantic states Ehrlichia chaffeensis, Ehrlichia canis Spring–Summer Cholestatic Doxycycline Human granulocytic anaplasmosis New England, North-Central, and Pacific states Anaplasma phagocytophilum Spring–Summer Cholestatic Doxycycline Tularemia South-East and South-Central (majority of cases in Missouri, Arkansas, Tennessee, Oklahoma, Kansas, Utah) Francisella tularensis Summer associated with arthropod and tick-borne disease Winter associated with animal contact Cholestatic Streptomycin or gentamicin Babesiosis Northeastern states Babesia microti Summer–Autumn Hepatocellular Azithromycin plus atovaquone Colorado tick fever Western states (Arizona, Colorado, Idaho, Montana, Oregon), Wasatch Sierra Nevada mountain ranges Coltivirus Spring–Summer Hepatocellular Symptomatic treatment TBRF Western states Borrelia turicatae, Borrelia hermsii, Borrelia parkeri Summer Hepatocellular Doxycycline Q fever Western states Coxiella burnetti Spring–early Summer Hepatocellular Doxycycline aTreatment duration and regimen may vary based on organ involvement (eg, cardiac or central nervous system), severity of illness, pregnancy status. Recommend following Centers for Disease Control and Prevention (CDC) guidance for comprehensive tick-borne disease treatment.1Abbreviations: RMSF, Rocky Mountain spotted fever; TBRF, tick-borne relapsing fever. LYME DISEASE Lyme disease is the most common vector-borne disease in the US. Borrelia burgdorferi, the causative agent, is an invasive spirochete and gives rise to hepatic injury through direct hepatocyte invasion and activation of humoral and cellular immunologic responses. Hepatic involvement is more common in early disseminated disease and in patients with erythema marginatum (66% vs. 34%, p = 0.002).2 Rarely, hepatological involvement is cited in patients without skin involvement.3 In the absence of underlying liver disease, 40% of patients present with at least 1 abnormal liver test and 27% with at least 2 abnormal tests which classically presents as mild transaminitis2(Table 2). However, it is important to note that aspartate aminotransferase and alanine aminotransferase elevation may indicate Lyme-associated myositis rather than underlying hepatic injury. Antibiotic treatment typically leads to the normalization of liver function tests within 3 weeks. In rare instances, Lyme disease can also present as granulomatous hepatitis and severe hyperbilirubinemia, however, in our literature review, there were no cases of liver failure or severe transaminitis. Table 2 - Characteristic liver function tests abnormalities observed in tick-borne diseases Tick References AST (% of n) ALT (% of n) ALP (% of n) Total bilirubin (% of n) PT (% of n) Lyme disease Steere et al4 (n = 314) 19% (36–251 U/mL) 15% (42–491 U/mL) NA NA NA Nadelman et al5 (n = 79) 18% (41–355 U/L) 26% (41–238 U/L) 17% (121–525 U/L) NA NA Horowitz et al2 (n = 115) 16% 27% 19% 3% NA Kazakoff6 (n = 73) 8% (49–161 U/L) 11% (58–428 U/L) 8% (150–357 U/L) 3% NA RMSF Middleton7 (n = 66) 76% (20–897 IU/L) 83% (21–3297 IU/L) 69% (22–40 μmol/L) 41% Helmick et al8 (n = 262) 37% NA 10% 13% NA Álvarez-López et al9 (n = 510) 66% fatal cases (151–408 IU/L) 30% nonfatal cases (80–215 IU/L) 65% fatal cases (69–146 IU/L) 29% nonfatal cases (47–92 IU/L) NA 66% fatal cases (2.4–5.7 mg/dL) 25% nonfatal cases (0.8–2.6 mg/dL) Q fever Sampere10 (n = 66) 40% 40% 30% NA NA Palmela et al11 (n = 32) 22% 23% 16% 15% NA Alarcón et al12 (n = 231) 42% 60% NA NA NA Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; NA, not available; PT, prothrombin time; RMSF, Rocky Mountain spotted fever. RMSF RMSF is a widespread rickettsial disease transmitted by Dermacentor ticks, associated with a 5%–10% case-fatality rate if left untreated. In terms of hepatic injury, several pathophysiological mechanisms have been suggested including direct infection of the endothelial lining, liver sinusoids, and portal vasculature. However, direct invasion of hepatocytes is not reported.13 Classically, this results in hyperbilirubinemia and concomitant mild transaminitis. Clinical presentation begins with prodromal symptoms including anorexia, fever, nausea, and vomiting followed by the appearance of rash 2–4 days after fever onset.7 In a study of 262 patients who died due to RMSF infection, hepatomegaly, and jaundice were found in 55% and 40% of patients, respectively.8 Jaundice is a strong predictor of mortality and is the combined result of biliary duct inflammation and hemolysis. EHRLICHIOSIS AND ANAPLASMOSIS Ehrlichia species are obligate intracellular gram-negative bacteria that can infect monocytes (human monocytic ehrlichiosis) or granulocytes (human granulocytic anaplasmosis). Human monocytic ehrlichiosis and human granulocytic anaplasmosis are transmitted by the Amblyomma and Ixodes ticks, respectively, with the latter having greater incidence in the US. Ehrlichia proliferates within hepatocytes thereby causing hepatic injury through inflammation and immunologic mechanisms. Hepatic involvement is present in >80% of cases manifesting as cholestatic hepatitis, focal necrosis, or granulomatous lesions usually evidenced by mild liver enzyme elevation, hyperbilirubinemia, and jaundice. Hepatosplenomegaly and liver failure may occur. The development of a rash is rare in human granulocytic anaplasmosis (1%–10%), however, occurs in 30%–60% of patients with human monocytic ehrlichiosis.14 In addition, the combination of leukopenia, thrombocytopenia, and cholestatic liver derangement distinguishes ehrlichiosis and anaplasmosis from other tick-borne diseases. TULAREMIA Francisella tularensis is a highly virulent gram-negative coccobacillus transmitted by a variety of routes including direct or indirect animal contact and arthropod bites. F. tularensis spreads through the lymphohematogenous route and replicates within macrophages. Hepatic injury manifests as coagulative necrosis, sinusoidal dilatation, and caseating granulomas.15 The arthropod-transmitted disease characteristically gives rise to ulceroglandular or typhoidal disease, the latter more frequently associated with nonspecific gastrointestinal symptoms. The most common hepatic manifestations include marked cholestasis and jaundice. Cholangitis, liver abscess, granulomatous hepatitis, and ascites have been reported. Elevated alkaline phosphatase is the predominant biochemical finding, although mild transaminitis is often present. In severe disease, rhabdomyolysis with renal failure may occur which can falsely elevate aspartate aminotransferase.16 BABESIOSIS Babesia species cause a malaria-like protozoal infection manifested by invasion of human erythrocytes and intracellular replication leading to a febrile hemolytic anemia. Clinical features develop 1–6 weeks after infection and include arthralgia and fatigue. Severe, life-threatening disease may occur in immunocompromised or splenectomized patients as the reticuloendothelial system is the primary defense mechanism against infection.17 The liver is generally spared, however, may be affected to a larger degree in splenectomized patients with the fulminant disease. Due to a shared Ixodes tick vector, co-infection with other tick-borne diseases may occur. Hepatosplenomegaly may occur although not as frequently as in ehrlichiosis. The degree of indirect hyperbilirubinemia reflects the severity of parasitemia and mild elevations in transaminases may be noted. Rarely, fulminant liver failure has been reported in the literature.18 COLORADO TICK FEVER Hepatic involvement in Colorado tick fever is uncommon and may rarely occur in late-stage disease. The precise mechanism is unknown and is thought to be related to immune complex deposition although direct viral invasion cannot be excluded. Gastrointestinal features are uncommon and may include abdominal pain and vomiting. The condition has a benign course and resolves with supportive treatment. TBRF TBRF may be caused by several Borrelia species that directly invade hepatocytes and rapidly replicate causing focal hepatic necrosis. TBRF is often misdiagnosed as Lyme disease due to the cross-reactivity of diagnostic assays and may be more appropriately detected with peripheral blood smears.19 Clinical features include nonspecific gastrointestinal symptoms with nausea and vomiting as the most common presentation. Gastrointestinal bleeding is common in the setting of thrombocytopenia although this is rarely severe. Hepatosplenomegaly, jaundice, hepatitis, and hepatic necrosis may occur with fulminant hepatic failure, a common cause of death in severe cases. Q FEVER Coxiella burnetti is a small, obligate intracellular gram-negative coccobacillus typically transmitted to humans following inhalation of dust contaminated with infected feces or contents of parturition from a myriad of mammalian reservoirs. Hepatological manifestations include focal hepatocellular necrosis and granulomatous disease with the classic appearance of “doughnut granulomas,” consisting of a circumferential fibrous ring surrounding a lipid core.20 Hepatic involvement includes acute hepatitis and granulomatous disease with evidence of mild liver enzyme elevation and elevated bilirubin. CONCLUSIONS Tick-borne diseases can cause varying degrees of liver damage that tends to be self-limited in most cases. Liver injury is most common in patients with ehrlichiosis, tularemia, and babesiosis. An algorithm for the evaluation of elevated liver enzymes in this setting is shown in Figure 1. A high index of suspicion based on exposure potential, geographic setting, exclusion of other causes of liver injury, and close working relationships between specialties such as infectious disease, gastroenterology, and hepatology are needed for appropriate management.FIGURE 1: Algorithm for evaluation of elevated liver enzymes in the setting of tick-borne diseases. *Risk factors for each pathogen will vary based on geographic region, seasonality, and vector. Refer to most up-to-date epidemiological data from the Centers for Disease Control and Prevention (CDC).1 **Clinical signs and symptoms will vary based on the particular tick-borne disease, considerable overlap exists. Abbreviation: TBRF, tick-borne relapsing fever.