A seasonal idiopathic hepatitis syndrome in horses presented to a Midwestern veterinary teaching hospital

Sandra D. Taylor Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN

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Janice E. Kritchevsky Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN

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Patrick Huang Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN

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Carla Olave Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN

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Sarah J. Waxman Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN

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Margaret A. Miller Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN

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Abstract

OBJECTIVE

To report history, clinical examination findings, clinicopathologic findings, diagnostic test results, treatment, and outcome in horses with a novel idiopathic hepatitis syndrome.

ANIMALS

13 client-owned horses.

PROCEDURES

Medical records of horses that were presented with fever and increased blood liver enzyme activity over a 16-month period were reviewed (December 1, 2020, to April 1, 2022). Collected data included signalment, history, clinical and clinicopathologic findings, diagnostic test results, treatment, clinical progression, and short-term outcome.

RESULTS

Affected horses were presented between December and April of each of the 2 seasons investigated. The majority of horses developed cyclic fevers over the course of 3 weeks, during which time histologic evidence of hepatitis was observed. Histologic lesions included hepatic necrosis, neutrophilic to lymphohistiocytic inflammation, biliary epithelial injury, and portal fibrosis. Systemic inflammation was evidenced by increased serum amyloid A concentration and leukon changes. No horse developed signs of hepatic insufficiency, and all horses clinically recovered. Return of serum activity of GGT to within the reference range occurred within 16 weeks in most horses. Histologic lesions remained evident up to 27 weeks after initial presentation in 1 horse.

CLINICAL RELEVANCE

Although an etiologic agent has not been identified, an apparently seasonal equine hepatitis syndrome was characterized by fever, systemic inflammation, increased liver enzyme activity, and histologic evidence of hepatitis. An infectious cause is suspected on the basis of histology and outcome.

Abstract

OBJECTIVE

To report history, clinical examination findings, clinicopathologic findings, diagnostic test results, treatment, and outcome in horses with a novel idiopathic hepatitis syndrome.

ANIMALS

13 client-owned horses.

PROCEDURES

Medical records of horses that were presented with fever and increased blood liver enzyme activity over a 16-month period were reviewed (December 1, 2020, to April 1, 2022). Collected data included signalment, history, clinical and clinicopathologic findings, diagnostic test results, treatment, clinical progression, and short-term outcome.

RESULTS

Affected horses were presented between December and April of each of the 2 seasons investigated. The majority of horses developed cyclic fevers over the course of 3 weeks, during which time histologic evidence of hepatitis was observed. Histologic lesions included hepatic necrosis, neutrophilic to lymphohistiocytic inflammation, biliary epithelial injury, and portal fibrosis. Systemic inflammation was evidenced by increased serum amyloid A concentration and leukon changes. No horse developed signs of hepatic insufficiency, and all horses clinically recovered. Return of serum activity of GGT to within the reference range occurred within 16 weeks in most horses. Histologic lesions remained evident up to 27 weeks after initial presentation in 1 horse.

CLINICAL RELEVANCE

Although an etiologic agent has not been identified, an apparently seasonal equine hepatitis syndrome was characterized by fever, systemic inflammation, increased liver enzyme activity, and histologic evidence of hepatitis. An infectious cause is suspected on the basis of histology and outcome.

Introduction

Hepatitis in horses is most commonly caused by ascending enteric bacterial infections,1,2 primary viral infections,3–6 or toxicosis.7–11 Ascending bacterial hepatitis is often associated with primary gastrointestinal disease such as large colon displacements or duodenitis, with inflammation into hepatic portal tracts and bile ducts observed histologically.12–14 Clinical signs of ascending bacterial hepatitis include fever, icterus, colic, and weight loss.1,2 Hepatitis viruses including equine parvovirus hepatitis (EqPV-H) and nonprimate hepacivirus (NPHV; also known as equine hepacivirus) are hepatotropic, with EqPV-H demonstrating a strong association with Theiler’s disease (ie, equine serum hepatitis).4–6,15 Theiler’s disease is associated with lymphocytic hepatitis and acute panlobular (massive) hepatic necrosis, with the majority of clinically affected horses exhibiting signs of liver failure at presentation.4,5,16 NPHV typically causes mild, subclinical hepatitis and is not associated with Theiler’s disease.17,18 Similarly, equine hepatitis B virus infection appears to cause subclinical hepatitis.3 Pyrrolizidine alkaloids (PA) are potent hepatotoxic compounds that are present in several plants that, when ingested by horses, can cause hepatitis and liver failure.10,11,19,20 Typical histological features of PA toxicosis include panlobular hepatic necrosis, megalocytosis in remaining hepatocytes, mild portal fibrosis, and bile duct proliferation with minimal inflammation.9 Subclinical cases may be histologically normal or have minimal piecemeal necrosis with death of individual hepatocytes at the lobular interface.9 Alsike clover and panicum grasses also contain hepatotoxins that can lead to hepatic necrosis and failure.21,22 Other less common causes of hepatitis in horses include fungal or bacterial hepatitis, equine infectious anemia virus, idiopathic hepatitis, and fumonisin or other mycotoxicosis.7,8,2325

Although fever and clinicopathologic evidence of systemic inflammation are common findings in horses with ascending bacterial hepatitis, horses with viral hepatitis and hepatotoxicosis are typically afebrile.1,2,4,10 Furthermore, ascending bacterial hepatitis is not typically associated with liver failure, in contrast to Theiler’s disease and hepatotoxicosis.2,4,5,10

Between January and March of 2021 and between December of 2021 and March of 2022, horses with fever and clinicopathologic evidence of hepatitis were presented to the Purdue University Veterinary Hospital (PUVH). Hepatitis was confirmed by histologic examination in all horses presented to the PUVH. Despite exhaustive efforts, a bacterial or viral cause could not be identified. The objective of the case series reported here was to report signalment, history, physical examination findings at admission, clinicopathologic findings, diagnostic test results, treatment, and outcome in horses with a seasonal idiopathic hepatitis syndrome.

Materials and Methods

Data collection

Medical records of horses that were presented to the PUVH between December 1, 2020, and April 1, 2022 (to include 2 winter seasons) were reviewed. Inclusion criteria included complete medical records, fever, increased serum GGT activity, and histologic evidence of hepatitis. Data collected from the records of each horse included age, breed, sex, history, physical examination findings on admission, histologic findings in liver biopsies, other diagnostic test results, treatment, clinical progression, and outcome. Serial CBCs, serum biochemical profiles, serum amyloid A (SAA) concentrations, and liver biopsies were obtained after admission in some horses to assess trends in inflammation, liver enzyme activity, and liver histology during the clinical course of the syndrome. Follow-up information was obtained within 1 week of manuscript submission through communication with owners or referring veterinarians. The university’s information technology department compared the number of historical admissions of equine hepatitis cases from the previous 5 years to the hepatitis cases described in this study to determine if the new cases represented a true increase. Historical diagnoses included cholangiohepatitis, Theiler’s disease, PA toxicosis, and mycotoxicosis.

Histologic examination

Ultrasound-guided 14-gauge needle core biopsies were performed in all 13 horses on initial presentation and/or follow-up evaluation. Biopsy specimens were submitted in formalin to the surgical pathology service at the Indiana Animal Disease Diagnostic Laboratory for histologic evaluation. After recognition of an apparently unique equine hepatitis syndrome, all slides were reviewed independently by 2 authors (PH and MAM) without knowledge of the horse’s identity, clinical presentation, or initial histopathology report. Histologic lesions were characterized and scored from 0 (not detected) to 4 for the following:

  • Hepatocellular necrosis: 1 = single necrotic focus or focal piecemeal necrosis; 2 = > 1 focus or widespread piecemeal necrosis; 3 = ≥ 1 focus/5-mm plus piecemeal necrosis; 4 = postnecrotic repair (eg, ductular reaction).

  • Biliary epithelial injury: 1 = hypertrophy; 2 = 2 to 5 ductular profiles/portal tract; 3 = > 5 ductular profiles/portal tract; 4 = ductular reaction.

  • Inflammation: 1 = mild or only segmental portal tract involvement; 2 = moderate and more widespread portal tract involvement; 3 = features of grade 2 plus multifocal hepatitis; 4 = severe in portal tracts and hepatic lobules.

  • Portal fibrosis: 1 = segmental with 2 to 3 collagen fiber layers; 2 = segmental with 4 to 6 collagen fiber layers; 3 = diffuse with 4 to 6 collagen fiber layers; 4 = diffuse with > 6 collagen fiber layers and extension into hepatic lobules.

Piecemeal necrosis was defined as hepatocellular death or loss at the limiting plate (ie, the interface between hepatic lobules and portal tracts). Biliary profiles per portal tract were quantified by counting the number of cross- or tangential sections through bile ductules. Ductular reaction was defined as a response to severe hepatocellular injury in which progenitor cells in portal tracts proliferate, forming tubular structures and differentiating into both hepatocytes and biliary epithelial cells. Any scoring discrepancies were resolved by simultaneous review of slides by 2 authors (PH and MAM) using a double-headed microscope.

Data analysis

Data were evaluated descriptively using ratios in this retrospective case series. Data are presented as median and range.

Results

Signalment and history

Thirteen horses met the inclusion criteria including 10 geldings and 3 mares (median age, 13 years; range, 3 to 30 years; Table 1). Two horses with clinical signs and clinicopathologic findings consistent with the idiopathic hepatitis syndrome were excluded due to owner refusal of liver biopsy collection. The number of affected horses that were presented in this time frame exceeded what was expected based on historical admissions by approximately 8 times. Additionally, other practices and institutions in the Midwest experienced a similar increase in horses presented with fevers and evidence of hepatic disease (PA Wilkins, DVM, PhD, College of Veterinary Medicine, University of Illinois, email, January 25, 2021; NM Slovis, DVM, Hagyard Equine Medical Institute, email, January 28, 2021; S Austin, DVM, College of Veterinary Medicine, University of Illinois, email, January 29, 2021; and H Schott, DVM, PhD, College of Veterinary Medicine, Michigan State University, email, March 11, 2021). Of the 13 horses in the study, 2 were from the same farm; all other cases were sporadic. Seven breeds were represented including 5 Quarter Horses, 2 Paint Horses, 2 Thoroughbreds, and 1 each of 4 other breeds (Warmblood, Morgan, Pony of the Americas, and American Miniature Horse). Fever (> 38.6 °C) and anorexia were reported as recent complaints in all horses (13/13), with colic reported in 2 of 13. Prior to presentation, administered treatments included flunixin meglumine (11/13), phenylbutazone (2/13), and antimicrobial drugs (4/13). All horses were referred to the PUVH due to recurrent fevers despite initial response to NSAIDs. Vaccination history was available for 10 horses, all of which were considered fully vaccinated against eastern and western equine encephalitis, tetanus, and West Nile virus on the basis of manufacturer recommendations. Six horses were fully vaccinated against Potomac horse fever, rabies, influenza, and equine herpesvirus.

Table 1

Histologic scoring of hepatic biopsy specimens from 13 horses for hepatocellular necrosis, biliary epithelial injury, inflammation, and portal fibrosis.

Horse No. Weeks postadmission (1st/2nd/3rd) Area (mm2; 1st/2nd/3rd) Hepatocellular necrosis (1st/2nd/3rd) Biliary injury (1st/2nd/3rd) Inflammation (1st/2nd/3rd) Fibrosis (1st/2nd/3rd)
1 15/23 25/13 1/0 2/2 1/0 1/1
2 0/27 11/16 2/0 3/2 3/1 3/2
3 0 7 4 4 3 3
4 0/17 7/30 3/1 2/2 3/2 1/1
5 0/2 8/18 3/3 3/3 3/3 3/2
6 18 13 1 2 2 2
7 0 12 3 2 3 1
8 0/16/21 15/27/19 2/2/1 3/2/2 2/1/1 3/2/1
9 0 35 3 2 3 1
10 0 24 1 2 1 2
11 0 25 1 2 1 2
12 0/17 11/27 3/3 2/2 3/3 1/1
13 0 14 3 3 3 3

For horses with > 1 histologic evaluation, data are entered as 1st/2nd/3rd.

See Materials and Methods for histologic scoring.

Clinical signs and clinicopathologic data at admission

Clinical signs at presentation included fever (7/13), tachycardia (> 44 beats per minute [bpm]; 8/13), lethargy (3/13), dehydration (3/13), and decreased borborygmi (4/13). The median rectal temperature, heart rate, and respiratory rate at admission were 39 °C (range, 38.1 to 40.7 °C), 48 bpm (range, 24 to 60 bpm), and 16 breaths per minute (range, 10 to 24 breaths per minute), respectively. At admission, a CBC and serum biochemical profile were available for all 13 horses while plasma fibrinogen concentration, sorbitol dehydrogenase (SDH) activity, and SAA concentration were available for 11, 7, and 6 horses, respectively. The most common CBC abnormalities at admission included lymphopenia (8/13), neutrophilia (6/13), and anemia (6/13). Toxic changes to neutrophil morphology were reported in 3 of 13 horses. The most common serum biochemical abnormalities included increased GGT activity (13/13; inclusion requirement) and hyperbilirubinemia (9/13). Increased ALP and AST activity were found in 3 of 13 and 1 of 13 horses, respectively. Increased plasma fibrinogen concentration, SAA concentration, and SDH activity were detected in 7 of 10, 5 of 6, and 4 of 7 horses, respectively.

Diagnostic tests

Hepatic biopsies were performed in all 13 horses as an inclusion requirement. A second follow-up biopsy was performed in 6 horses and a third follow-up biopsy in 1 of the 6. Histologic scoring for hepatocellular necrosis, biliary epithelial injury, inflammation, and portal fibrosis is summarized (Table 1). Histologic lesions ranged from mild (Figure 1) to severe (Figure 2). Hepatocellular necrosis was a feature of all initial biopsy specimens but was not detected in 2 of 6 horses on follow-up hepatic biopsy. Increased numbers of biliary profiles were observed in all horses, and ductular reaction was observed in 1 horse. Random foci of hepatic necrosis were infiltrated by neutrophils and/or macrophages, whereas inflammation at the lobular interface with portal tracts was lymphohistiocytic. Inflammation scores decreased in 5 of 6 horses with follow-up biopsy. Biliary injury and fibrosis scores did not decrease more than 1 grade level or at all on repeat biopsy. In all horses, hepatocytes were generally swollen with brown globular cytoplasmic pigment in Kupffer cells and/or macrophages. Rare histologic lesions included an eosinophilic granuloma in a follow-up biopsy from horse 4 and eosinophilic portal inflammation from horse 6.

Figure 1
Figure 1

Photomicrographs of a hepatic biopsy specimen from horse 1, 15 weeks after initial presentation. A— Lesions are not apparent at low magnification. H&E stain; bar = 500 μm. B—A rare focus of necrosis is infiltrated by macrophages and lymphocytes. H&E stain; bar = 25 μm. C—A portal tract has only mild biliary epithelial injury, inflammation, and fibrosis. H&E stain; bar = 50 μm.

Citation: Journal of the American Veterinary Medical Association 261, 2; 10.2460/javma.22.08.0368

Figure 2
Figure 2

Photomicrographs of a hepatic biopsy specimen from horse 3 on initial presentation. A—Notice diffuse expansion of portal tracts. H&E stain; bar = 500 μm. B—A portal tract (left) is expanded by ductular reaction, lymphohistiocytic inflammation, and fibrosis that extend into the hepatic lobule (right). Notice the brown pigment (lipofuscin) in hepatocytes near the portal tract and a focus of necrosis (asterisk). H&E stain; bar = 50 μm.

Citation: Journal of the American Veterinary Medical Association 261, 2; 10.2460/javma.22.08.0368

Aerobic and anaerobic hepatic microbial cultures were negative in 3 of 3 and 1 of 1 horses tested, respectively. Molecular diagnostic testing was performed on sera or liver in all 13 horses. Equine parvovirus-hepatitis was negative in serum from 9 of 12 horses (positive in 3/12) and negative in liver from 11 of 12 horses (positive in 1/12). Nonprimate hepacivirus was not detected in any serum or liver sample. Rickettsia spp PCR (primers for which were expected to detect Neorickettsia findlayensis) of liver was negative in 4 of 4 horses. Bartonella spp PCR of liver was negative in 2 of 2 horses. Canine and equine adenovirus PCR of liver was negative in 2 of 2 horses. Liver, nasal swabs, nasopharyngeal swabs, and/or feces were negative for SARS-Cov-2 PCR in 2 of 2 horses. Virus isolation and electron microscopy of liver were negative for detection of organisms in 1 of 1 horse. Fecal PCR was negative for equine coronavirus, Clostridium difficile toxin A and B genes, Lawsonia intracellularis, Neorickettsia risticii, and Salmonella spp in 5 of 5 horses. Electron microscopy of feces was negative for detection of bacteria or viruses in 2 of 2 horses. Nasal swab PCR was negative for equine herpesvirus 1 and 4, equine influenza A, Streptococcus equi spp equi, and equine rhinitis A and B viruses in 2 of 2 horses. Whole blood was negative for Anaplasma phagocytophilum PCR in 1 of 1 horse. Horses were also negative for Leptospira spp as assessed by blood and urine PCR in 2 of 2 horses.

Treatment

Seven of 13 horses were hospitalized for treatment, the median duration of which was 8 days (range, 3 to 17 days). All hospitalized horses were treated with flunixin meglumine (Prevail; 1.1 mg/kg, IV or PO, q 12 to 24 hours) as needed for fevers. Dipyrone (Zimeta; 30 mg/kg, IV, q 12 to 24 hours) or acetaminophen (Tylenol; 10 to 20 mg/kg, PO) was administered to 4 of 7 or 1 of 7 hospitalized horses, respectively, when rectal temperatures exceeded 38.9 °C 6 hours after flunixin meglumine administration; 1 horse received both. Antimicrobial drugs were administered to 2 of 7 hospitalized horses. One horse was treated with ceftiofur crystalline free acid (Excede; 6.6 mg/kg, IM, q 4 d for 2 doses), and 1 horse was treated with trimethoprim sulfamethoxazole (SMX/TMP; 30 mg/kg, PO, q 12 h for 14 days). Omeprazole (GastroGard; 1 to 4 mg/kg, PO, q 24 h) was administered to 3 of 7 hospitalized horses.

Progression

Cyclic fevers were observed in 11 of 12 horses with a maximum of 4 fever cycles observed (horse 5). The duration of reported or observed fever cycles ranged from 2 to 14 days each. The average duration of normothermia between fever cycles was 6 days. The median peak rectal temperature recorded was 40.5 °C (range, 39.4 to 41.8 °C; Table 2).

Table 2

Peak rectal temperature; serum amyloid A (SAA) concentration; GGT, AST, ALP, and sorbitol dehydrogenase (SDH) activity; and total bilirubin concentration during hospitalization in 13 horses with an idiopathic hepatitis syndrome.

Horse No. Rectal temperature (°C) 36.7–38.6 SAA (mg/dL) < 5 GGT (IU/L) < 46 AST (IU/L) 206–810 ALP (IU/L) 109–331 SDH (IU/L) < 6 Total bilirubin (mg/dL) < 0.10–2.60
1 40.3 75 602 225 6 4.4
2 41.8 884 366 920 902 75 6.3
3 40.5 630 320 702 474 2.9
4 39.9 561 98 800 290 9 10.2
5 40.8 931 203 791 207 19 5.4
6 40.2 968 367 605 415 2 2.9
7 40.6 1,032 106 620 181 4.4
8 40.6 0 400 387 569 3 1.3
9 40.3 5 87 493 143 3 1.0
10 40.1 538 124 648 252 11 6.4
11 39.4 6 279 541 314 3 3.6
12 41.6 802 197 830 533 34 3.3
13 41.8 525 113 589 334 7 5.3
Median 40.5 596 197 620 314 7 4.4
Range 39.4–41.8 0–1,032 75–400 387–920 143–902 2–75 1.0–10.2

Peak values among variables for each horse did not necessarily occur on the same day. Reference range is bolded and italicized.

— = Not measured.

Subsequent CBCs, biochemical profiles, and plasma fibrinogen concentrations were performed in all horses with the number of each additional test ranging from 1 to 10/horse. Serum amyloid A concentrations were performed in all 13 horses after admission. Peak concentrations of relevant clinical and laboratory variables are presented (Table 2). In 9 of 13 horses, serial biochemical profiles were performed until GGT activity normalized. Horse 12 still had increased GGT activity (78 IU/L) at the time of manuscript preparation. Horses 6, 7, and 8 were lost to follow-up. Among the 9 horses with normalized GGT activity, the median time from admission to GGT normalization was 110 days (range, 43 to 162 days) and the median time from peak GGT activity to normalization was 107 days (range, 37 to 161 days).

Outcome

All horses recovered clinically and returned to previous work. Of the 11 horses with 2 to 4 fever cycles, the median time from the first to last day of fever was 17 days (range, 12 to 49 days). At the time of manuscript preparation, all horses not lost to follow-up were reported to be in good health with no clinical evidence of fever or hepatic disease.

Discussion

An idiopathic equine hepatitis syndrome was identified in horses that were presented to the PUVH over two 4-month periods in 2021 and 2022. Given the presence of high fevers that were biphasic in the majority of affected horses, along with evidence of systemic inflammation and histologically confirmed multifocal (random) hepatitis, an infectious pathogen was the most likely cause of this syndrome.

All hepatic biopsy specimens had varying degrees of hepatocellular necrosis (piecemeal and/or multifocal), biliary epithelial injury, neutrophilic to lymphohistiocytic inflammation, and portal fibrosis. These lesions are features of chronic hepatitis that overlap with those seen in humans and dogs, specifically the piecemeal necrosis (ie, interface hepatitis), biliary injury, mononuclear portal inflammation, and fibrosis.26 Multifocal hepatic necrosis is nonspecific but common in infectious diseases.26 Whereas piecemeal necrosis may be self-perpetuating without the need for continued presence of the stimulus, multifocal hepatic necrosis is considered an acute response to the presence of the etiologic agent. This finding, along with persistence of histologic lesions up to 27 weeks after initial presentation, sparks concern about an ongoing infection. The time frame for full resolution of hepatic lesions is unclear and requires further follow-up evaluation.

The many causes of chronic hepatitis include hepatotropic infectious agents, toxins, idiosyncratic drug reactions, metabolic disease, and autoimmune disease. In humans, chronic hepatitis is usually the result of infection by hepatotropic viruses, whereas in dogs, the underlying cause often remains unknown (idiopathic). Equine hepatotropic viruses rarely cause clinical disease and include EqPV-H and NPHV. EqPV-H is associated with equine serum hepatitis (Theiler’s disease), most commonly manifesting as acute and fatal hepatic failure due to massive loss of hepatocytes.16,26 Although EqPV-H was identified via PCR in the sera (but not liver) of 2 horses and serum and liver of 1 horse, these findings were likely incidental due to common prevalence. Expected clinicopathologic features of a horse with liver failure include decreased albumin concentration, decreased BUN concentrations, and decreased blood glucose concentration; none of these abnormalities were evident in any horse in our study. Given the presence of fever and lack of liver failure in any horse, this was inconsistent with Theiler’s disease.4–6 Global surveillance studies in clinically normal horses have demonstrated the molecular prevalence of EqPV-H in sera between 4.4% to 17%.6,2729 The molecular prevalence of EqPV-H in liver among healthy horses is unknown. NPHV mostly causes mild transient subclinical hepatitis, although chronic hepatopathy has been reported in association with infection in 2 horses; the exact pathophysiology or clinical significance of this virus has not been fully elucidated.15 NPHV was not identified via PCR or viral isolation in any horse. Given the relatively high and cyclic fevers, histopathology findings, and positive outcome despite lack of antibiotic treatment in several horses, it is possible that an as-yet-undiscovered hepatitis virus is responsible for this syndrome.

Bacterial causes of chronic hepatitis in adult horses are uncommon but may be a result of ascending infection via the common bile duct, portal vein, or systemic bacteremia. Bacterial cultures (anaerobic and aerobic) and PCR for various bacterial agents, including Salmonella spp, Streptococcus equi spp equi, Bartonella spp, and Leptospira spp, were negative in tested horses. It is regrettable that bacterial culture of the liver was only submitted in 3 horses, as this could have significantly impacted the study conclusions.

Hepatotoxins, such as PA, aflatoxins, or fumonisin B1 to name a few, are a major cause of liver injury in horses. However, multifocal hepatic necrosis is not typical of hepatotoxicosis. Instead, degeneration or necrosis tends to be zonal and inflammation is minimal to mild.26 In addition, affected horses are seldom febrile.

Interestingly, piecemeal necrosis is often a prominent feature of immune-mediated or autoimmune hepatocyte necrosis in humans.30 Although autoimmune hepatitis in veterinary species is poorly characterized, it cannot be excluded as a possible cause for chronic hepatitis in the horse. It should be noted that these horses recovered clinically without the use of corticosteroids. The eosinophilic inflammation noted in only 2 horses was considered unrelated to the other hepatic lesions. It could have reflected a hypersensitivity reaction to parasites or other allergens, but no histologic evidence of a particular etiologic agent was observed.

GGT is a transmembrane protein expressed predominantly by the biliary epithelium in the liver, increased activity of which was the most consistent biochemical abnormality in all horses (given the case inclusion criteria). Elevated serum GGT activity is sensitive for biliary epithelial hyperplasia secondary to damage, injury, or obstruction (cholestasis) to the biliary system.31 Indeed, biliary hyperplasia was noted in the majority of horses, which can explain the consistent GGT elevations. Although “plugs” of bile were not seen in canaliculi microscopically, these are often lost during histologic processing of 1-mm core biopsy specimens. The biliary hyperplasia and cholestasis in these horses were suspected to be secondary to hepatocellular injury and not from a bile duct obstruction, consistent with serum biochemical increases in unconjugated rather than conjugated bilirubin concentrations. In horse 8, there was an increase in serum GGT activity (from 86 to 138 IU/L) at the time of the third biopsy, which suggests continued cholestasis and/or biliary injury that might have been missed in the examined biopsy specimen due to the limited tissue size from a needle core biopsy; this horse was then lost to follow-up. Increased SDH activity was documented during the course of disease in nearly two-thirds of cases, supporting the presence of hepatocellular necrosis in some cases. However, the degree to which activity increased varied widely and did not always correlate with histology findings. For example, horse 2 had the highest recorded SDH activity (75 IU/L) with a high histologic score of 3 for hepatocellular necrosis, but horse 9 had normal SDH activity (3 IU/L) with the same histologic score (3) for hepatocellular necrosis. For both horses, the SDH activity and biopsy were evaluated within 48 hours of each other. Given the 12-hour half-life of SDH, these results suggest that SDH activity might not be sensitive enough to detect hepatocellular necrosis in some cases.32 Increased AST activity was rare with only mild increases, possibly due to missed peak window levels.

The majority of affected horses responded to NSAID therapy during febrile episodes, but some horses required additional antipyretic treatment. It is unclear whether antimicrobial treatment was indicated. Four of 13 horses received antimicrobial drugs prior to presentation, and 2 different horses received antimicrobial drugs during hospitalization. Antimicrobial treatment did not appear to affect the clinical course of disease, but case numbers were limited. It is possible that a longer duration of antimicrobial therapy (ie, > 2 weeks) might have sped recovery or prevented subsequent fever cycles. The presence of neutrophils in the majority of liver biopsy samples suggested that bacterial infection was possible and might have responded to long-term antibiotics. Although horses were hospitalized early during investigation of this apparent outbreak, hospitalization was considered unnecessary for horses that could have been monitored closely and treated at the farm. Thus, the duration of hospitalization decreased for cases that were presented later in the period of case presentations.

Limitations of this case series included the small number of horses in the study and limited number of liver biopsy procedures that were allowed. Horses with compatible clinical signs that were pregnant or in active race training were often not biopsied due to client or trainer concerns surrounding the biopsy procedure itself; this precluded inclusion of horses that were presented to a private practice in Kentucky (NM Slovis, DVM, Hagyard Equine Medical Institute, virtual discussion, March 30, 2021). Also, given that the majority of affected horses were not clinically sick enough to require hospitalization, it was difficult to recruit a large number of cases and most clients declined liver biopsy rechecks to assess progression of disease. Two clients declined even a single liver biopsy procedure, excluding horses from the study that were likely true cases. Furthermore, there was variation in frequency and postadmission timing of follow-up physical examinations and clinicopathologic assessments. True peaks in systemic inflammatory markers and liver enzyme activities might have been missed. Likewise, random foci of hepatic necrosis were usually few and may not have been included in small hepatic biopsy specimens. Finally, case series were self-selected and thus subject to selection bias. This is particularly true in this instance as horses exhibited nonspecific signs. Additionally, because cases were assessed retrospectively, we were dependent on the accuracy of medical record entries.

To summarize, an apparently seasonal idiopathic hepatitis syndrome between December of 2020 and April of 2022 was investigated. Despite extensive diagnostic testing, an etiology has not been identified at the time of manuscript submission. Although an extensive epidemiological survey of all reported cases in the Midwest is necessary to rule out common factors among horses that might indicate a specific source, no common thread was recognized in these 13 cases. Horses responded clinically to administration of NSAIDs and did not require antibiotic treatment. Although it is unknown whether affected horses will experience recrudescence or liver failure in the future, no affected horses from the first season demonstrated either by the time of publication. Screening of healthy herd mates for increases in liver enzyme activity is warranted, and continued investigation into the etiology and pathophysiology of this syndrome is critical. In addition to histology, culture and next-generation sequencing of liver biopsy specimens from affected horses might be instrumental in discovering the etiology of this syndrome.

Acknowledgments

This research was supported by the USDA National Institute of Food and Agriculture (Hatch Project No. IND020786). The authors declare that there were no conflicts of interest.

The authors thank Drs. Laurent Couetil, Stacy Tinkler, Caroline Gillespie-Harmon, Amanda Farr, Jose Goni, and Jenni Auvinen for their clinical expertise in case assessment and management; Drs. Kenitra Hendrix, Rebecca Wilkes, and Maria Cooper for facilitating SARS-Cov-2 testing; Drs. Gabriele Landolt and Toby Pinn-Woodcock for facilitating molecular diagnostic testing; and Dr. Thomas Divers for consulting.

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