Hepatology

Canine Chronic Hepatitis: Diagnosis & Treatment

Canine Chronic Hepatitis: Diagnosis & Treatment
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Yuri Lawrence, DVM, MA, MS, Diplomate ACVIM
Jörg Steiner, MedVet, DrMedVet, PhD, Diplomate ACVIM & ECVIM
Texas A&M University

Chronic hepatitis is the most common liver disease in dogs. The World Small Animal Veterinary Association Liver Standardization Group has published standards for diagnosis of the various forms of chronic hepatitis.1 This article reviews the current literature on diagnosis and treatment of canine chronic hepatitis.

PROFILE

Chronic hepatitis is characterized by hepatocellular apoptosis or necrosis, a variable mononuclear or mixed inflammatory cell infiltrate, regeneration, and fibrosis on histopathologic examination.1

Predisposition
The Doberman, West Highland white terrier, Labrador retriever, Skye terrier, American cocker spaniel, English cocker spaniel, standard poodle, and Bedlington terrier breeds are predisposed to chronic hepatitis.2

Causes
In most cases of canine chronic hepatitis, the cause is unknown. Known causes are outlined in Table 1.3-9 The cause, if known, should precede the term chronic hepatitis.

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INITIAL FINDINGS

Clinical Signs
Patients with chronic hepatitis often present with nonspecific clinical signs, although more specific signs may occur in patients with advanced disease (Table 2). Some affected dogs are asymptomatic at presentation, and clinical signs may be inapparent in patients with compensated advanced disease.

Physical Examination
Physical examination findings for chronic hepatitis are nonspecific, often normal and, in most cases, do not provide any information to identify the affected system unless the patient has jaundice (Table 2). Laboratory investigation is required to further evaluate patients for chronic hepatitis.

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Clinicopathologic examination is an important component of screening for evidence of chronic hepatitis and concurrent disease, and evaluating the systemic status of the patient.

 

LABORATORY FINDINGS

A complete biochemical profile, complete blood cell count, and urinalysis are generally adequate to screen for abnormalities.

Hepatic Abnormalities
Enzyme Activities & Bilirubin. Particular attention should be given to any elevation of hepatobiliary enzyme activities and bilirubin:

  • Elevated total serum bilirubin concentration has beenidentified as a negative prognostic indicator.12
  • Increased hepatobiliary enzyme activities, suchas alanine aminotransferase and aspartate aminotransferase, are consistent with hepatocellular damage.
  • Variable degrees of elevated hepatobiliary enzyme activities, such as alkaline phosphatase and gamma- glutamyl transpeptidase, are consistent with cholestasis.
  • Disturbances in markers of hepatocellular damage often predominate in dogs with chronic hepatitis, with 90% of patients demonstrating elevated serum alanine aminotransferase activity.13

Serum hepatobiliary enzyme activities may be normal, or only mildly increased, in patients with end-stage chronic hepatitis; therefore, even mild elevations may be significant, if persistent and when other potential causes have been excluded. Since dogs with significant liver disease can be clinically silent, in those with elevated liver enzyme activities that persist longer than 4 to 6 weeks, we recommend screening for an underlying etiology.

There may be additional evidence of hepatic insufficiency depending on disease severity:

  • Decreased serum albumin, cholesterol, bloodurea nitrogen (BUN), glucose (rare), or hyperbilirubinemia may reflect hepatic insufficiency or end-stage cirrhotic change.
  • These changes must be distinguished from different or concurrent abnormalities, such as protein-losing enteropathy, decreased protein intake, polyuria (increased renal excretionof BUN), or hemolytic anemia (prehepatic hyperbilirubinemia).

Liver Function. Specific tests of liver functionare often warranted, but there is no consensus on which liver function test is most appropriate. The most commonly performed test in the U.S. and, in our opinion, the most useful test (in the absence of hyperbilirubinemia), is the provocative serum total bile acids test, which includes a fasted preprandial and 2-hour postprandial (provoked) serum total bile acid concentration.

Other liver function tests include fasted preprandial serum total bile acid concentration, postprandial serum total bile acid concentration, and basal plasma NH3 concentration.

Hematologic Abnormalities
Blood Cells. Nonregenerative anemia due to decreased mobilization of systemic iron stores may be present in dogs with chronic hepatitis; regenerative anemia may be present if associated with gastrointestinal blood loss. Morphologic erythrocyte abnormalities due to altered lipoprotein content may also be seen.

Coagulation. Coagulation status should be assessed because altered hemostasis can contribute to clinical disease and may affect diagnostic testing options. Available tests are listed in Table 3, but no individual test predicts clinically significant bleeding and, thus, evaluation of primary and secondary hemostasis is recommended. Abnormalities can result from hepatic synthetic failure, vitamin K deficiency, disseminated intravascular coagulation, and qualitative or quantitative platelet defects.

Serology. Serology for leptospirosis can be submitted to determine the potential role of this pathogen.

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Learn More

In this issue, read Canine Leptospirosis: (Still) An Emerging Infection? written by Dr. Richard Ford.

ULTRASONOGRAPHY

Complete abdominal ultrasonography is an essential component of further diagnostic evaluation
that allows screening for concurrent disease and acquisition of bile.

• In chronic hepatitis, the liver is variable and can be normal upon examination.

• Sonographic changes consistent with chronic hepatitis include uniform increases in liver echogenicity, decreased distinction of portal vein margins, and normal to small liver size.

• The liver parenchyma, biliary tree, portal vein, and peritoneum should be assessed for abnormalities, acquired shunting, and presence of free peritoneal fluid.

CHOLECYSTOCENTESIS

Cholecystocentesis to acquire bile for cytologic evaluation and aerobic/anaerobic bacterial culture and sensitivity should be routinely performed in patients suspected of having chronic hepatitis. This technique can be safely performed via ultrasound guidance, laparoscopic guidance, or direct visualization during laparotomy (Figure 1).

Bacterial cholecystitis can result in clinical signs and clinicopathologic anomalies indistinguishable from chronic hepatitis and, thus, exclusion of this disease is an important component of the diagnostic evaluation.

Figure 1 Liver Laproscopy Cholecystocentesis Zoom

FIGURE 1. Laparoscopic-assisted cholecystocentesis permits safe acquisition of bile for diagnostic evaluation. Courtesy Dr. Romy Heilmann, Texas A&M University

DIAGNOSTIC LIVER BIOPSY

Liver biopsy is essential for establishing a definitive diagnosis in dogs suspected of having chronic hepatitis. Several biopsy techniques are available for acquiring histology-grade liver tissue; however, fine-needle aspiration is NOT adequate for diagnosis of any type of inflammatory liver disease.

Histopathologic diagnosis of chronic hepatitis requires demonstration of the characteristic components: hepatocellular necrosis or apoptosis, mononuclear or mixed inflammatory cell infiltrate composed primarily of lymphocytes and plasma cells, regeneration, and fibrosis.1

• Pattern and distribution of characteristic components of chronic hepatitis are variable.

• Disease severity is determined by amount of inflammation present and extent of hepatocellular necrosis and apoptosis.

• Stage of disease is determined by the extent and pattern of fibrosis.

• Qualitative increases in copper may be detected with special stains if levels exceed 400 ppm. The pattern of copper accumulation can also provide additional information about the disease process, with qualitative staining techniques revealing that:

  • »  Cholestatic diseases result in periportal (zone 1) copper accumulation
  • »  Copper-associated chronic hepatitis results in centrilobular (zone 3) accumulation.

Percutaneous Ultrasound-Guided Needle Biopsy

Percutaneous ultrasound-guided needle biopsy uses an automated, semi-automated, or manual biopsy needle to acquire hepatic tissue. Percutaneous TruCut (carefusion.com) liver biopsies require ultrasound guidance and may be limited by a small liver or small patient size. Particular care should be taken to ensure adequate sampling (3–6 tissue specimens/samples; 14-gauge for large/medium dogs or 16-gauge for small dogs).

Advantages include that the technique can be performed under sedation, is minimally invasive, and isolated lesions within the hepatic parenchyma can be specifically sampled. Disadvantages include relatively smaller biopsy samples and inability to control hemorrhage directly. Sampling may be limited if the liver or the patient is of small size.

Laparoscopic Biopsy
Laparoscopic liver biopsy is performed under general anesthesia, and the liver is sampled with biopsy forceps. Gross examination of the liver and associated structures and targeted sampling of multiple identified lesions can be performed (Figure 2). After sample acquisition, the biopsy sites can be visually inspected for hemorrhage (Figure 3).

Advantages of this technique include direct visualization of the liver; relatively large tissue samples; ability to control hemorrhage directly with a palpation probe or a hemostatic agent, such as gel foam; and access to multiple liver lobes for sampling. Disadvantages include need for specialized equipment and specific skills, general anesthesia, and cost.

Figure 2 Liver Laproscopy Gross Image

FIGURE 2. Laparoscopic image of the liver in 7-year-old intact male Labrador retriever with chronic hepatitis and marked fibrosis. Note gross discoloration and nodular remodeling. Courtesy Dr. Romy Heilmann, Texas A&M University

Figure 3 Liver Laproscopy Post Biopsy

FIGURE 3. Laparoscopic image of liver after biopsy; demonstrates normal degree of postprocedural hemorrhage with normal coagulation.

Wedge Biopsy
Wedge biopsy by laparotomy can be performed by transfixation or biopsy punch. Advantages and disadvantages of this technique are similar to those for laparoscopy. Additional consideration for this technique is degree of invasiveness; however, it can be combined with other surgical procedures in the abdomen.

Other Biopsy Techniques
A transjugular liver biopsy technique has been recently described in dog cadavers but due to the high potential complication rate, which included perforations of the liver capsule in 13 of 16 dogs (81%), further studies are needed before this technique can be recommended.14

BIOPSY TECHNIQUE & EVALUATION

Biopsy Technique
All techniques suffer from sampling artifact and, thus, multiple samples should be acquired and multiple lobes biopsied. A recent study reported that if the liver biopsy specimen contains at least 3 to 12 portal triads, all biopsy techniques carry a similar diagnostic utility.15

Histopathologic Evaluation

Liver tissue samples should be submitted for histopathologic evaluation (Figure 4):
• Routine stains include hematoxylin–eosin.

• Special stains to characterize fibrosis or cirrhoticchanges include Sirius red, Masson trichrome stain, van Gieson stain, and the reticulin stain according to Gordon and Sweet.1

• Additional stains may also be used to detect certain substances, such as:

  • »  Copper (rubeanic acid or rhodanine stain)
  • »  Iron (Perls’ iron stain)
  • »  Glycogen (periodic acid–Schiff stain).

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Tissue Preparation

Additional special stains, immunohistochemical techniques, and polymerase chain reaction techniques can be performed on formalin-fixed tissue but provide better results in unfixed frozen tissue; therefore, an additional biopsy specimen should be freshly frozen.

Approximately 1 gram of fresh liver tissue in a serum blood tube is required for atomic absorption analysis; however, formalin-fixed tissue may also be submitted for copper quantification. Copper quantification and aerobic/anaerobic bacterial culture and sensitivity should be considered a routine part of the diagnostic evaluation.

Biopsy Concerns & Contraindications
Coagulation Concerns
Hemorrhage is a risk of all liver biopsy techniques and, thus, assessment of coagulation status is required despite the relative insensitivity of the available coagulation measures for predicting clinically significant bleeding. Postprocedural indications monitoring for hemorrhage is advised, with serial assessment of packed cell volume. Patients should be kept inactive for 6 to 8 hours after biopsy collection.

Biopsy Contraindications
Coagulation testing for laboratory analysis should be performed no more than 24 hours before liver biopsy because coagulation variables can change quickly in dogs with chronic hepatitis.Sampling of the liver is contraindicated if a severe coagulopathy is present (prolonged BMBT, platelet count < 80,000, PT/partial thromboplastin time prolonged > 1.5–2× normal). In some patients, however, coagulation measurements can be corrected with vitamin K supplementation, platelet transfusion, desmopressin acetate, or administration of fresh frozen plasma.

THERAPEUTIC APPROACH

The initiating factor in most cases of chronic hepatitis remains unknown. General principles guiding the treatment of idiopathic canine chronic hepatitis include (Table 4):

• Immunosuppressive therapy to resolve or control the inflammatory process

• Antioxidant therapy to prevent oxidative stress

• Antifibrotic therapy to inhibit fibrosis.

Available evidence suggests that humans and dogs have similar mechanisms for hepatic fibrosis in chronic hepatitis; thus, most treatment recommendations are extrapolated from the human literature.16,17 Compliance is essential for treatment success. Therefore, facilitating drug administration by limiting the number of medications to those most appropriate is prudent.

Symptomatic Therapy
Treatment of canine chronic hepatitis in most cases is symptomatic, supportive, and aimed at slowing progression of fibrosis (Table 4):

  • Nausea: Antiemetic therapy
  • Gastrointestinal ulceration: Appropriate antacid therapy
  • Portal hypertension: Inhibition of renin-angiotensin system
  • Hepatic encephalopathy: Appropriate dietary, probiotic, antimicrobial, and lactulose therapy.

Exceptions to limiting treatment to symptomatic therapy include:

  • Copper-associated chronic hepatitis: Specifictreatment includes low-copper diet, copper chelator, and potentially increased alimentary zinc
  • Infection-associated chronic hepatitis: Appropriateuse of antimicrobial agents
  • Drug-associated chronic hepatitis: Withdrawal of drug.

Immunosuppressive Therapy

Corticosteroid therapy with prednisone/prednisolone is the most common immunosuppressive medication used in dogs with chronic hepatitis. It has been shown to prolong survival, improve hepatic histologic changes, and induce remission.18,19 Adjunctive immunosuppressive therapy, such as leflunomide, can be added for steroid-sparing effects and/or additional immunosuppression to achieve disease remission.

In our opinion, remission is best determined by repeat liver biopsy. Serial monitoring every 2 weeks for normalization or marked reduction of alanine transaminase activity can be used as a surrogate marker of disease remission and to indicate repeat liver biopsy. Glucocorticoids frequently result in variable increases in alanine transaminase, alkaline phosphatase, and gamma-glutamyl transpeptidase activity; therefore, a relative significant decrease or normalization in alanine transaminase activity is often used in lieu of a second liver biopsy.

Antioxidant Therapy

The use of antioxidants as an adjunct to standard therapy is advocated to reduce hepatic injury and fibrosis in dogs with chronic hepatitis.20

• Studies of human patients with chronic hepatitis have documented that those with persistent oxidative stress benefit from antioxidant supplementation.21–24

• Glutathione, a potent antioxidant, has been reported to be decreased in dogs with necroinflammatory liver disease.25

• Vitamin E, S-adenosylmethionine, silibinin, N-acetylcysteine, and ursodeoxycholic acid are antioxidants commonly used as ancillary treatments in dogs with chronic hepatitis. In various studies, these nutraceuticals show inhibition of hepatic stellate cell activation, protection of hepatocytes from apoptosis, and attenuation of experimental liver fibrosis.26-28

• Veterinarians should be aware, however, that limited to no evidence supports the general use of antioxidants in preventing or treating chronic hepatitis, and few studies document beneficial effects of these antioxidants in vivo.

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Antifibrotic Therapy
There is no standard treatment for hepatic fibrosis. Experimental studies have identified targets to inhibit fibrosis in rodents, but the efficacy of most treatments has not been investigated in dogs.17 Also, the need to perform serial liver biopsies to accurately assess changes in liver fibrosis makes studies documenting treatment efficacy difficult.

The development of reliable noninvasive markers for liver fibrosis may enhance the management of these patients. Drugs with theoretical and limited experimental evidence for the treatment of fibrosis include colchicine, corticosteroids, penicillamine, zinc, angiotensin inhibitors, and angiotensin-receptor blockers.13,19,29,30

However, the clinical utility of colchicine for the reversal or prevention of hepatic fibrosis is limited, and because of the associated adverse effects, which include vomiting, diarrhea, and inappetance, we do not recommend routine use of this drug.

Protein Restriction
Protein restriction should be limited to the maximum tolerated level that prevents signs of hepatic encephalopathy; therefore, it may not be appropriate to start with the severe protein restriction provided by a prescription liver diet.

If protein restriction is required, diets that contain moderate amounts of protein, such as prescription renal diets and geriatric diets, may be suitable alternatives to a prescription liver diet. Diets may also be supplemented with high-quality protein, such as egg whites.

A consultation with a board-certified veterinary nutritionist may be necessary for patients with comorbid conditions or those in which homemade diets are indicated.

Anticopper Therapy
Anticopper drug therapy is generally reserved for cases with documented primary or secondary excess copper accumulation.

• The chelator, penicillamine, is typically used, and has additional anti-inflammatory and antifibrotic effects.

• Trientine can serve as an alternative if penicillamine is not tolerated.

• Copper chelators should be used for 3 to 6 months before a second liver biopsy is performed to ensure adequate disease remission and normalization of copper levels; then followed by zinc therapy, if appropriate to prevent copper reaccumulation.

• Zinc toxicity can result from oral zinc administration; periodic monitoring of blood zinc concentration is recommended with use of elemental zinc therapy.

PROGNOSIS

The prognosis for dogs with chronic hepatitis varies. Median survival durations of 18.3 to 36.4 months have been reported. However, patients with hypoalbuminemia, hypoglycemia, prolonged clotting times, bridging fibrosis, and ascites have shorter survival times.2,11,18,31

Early diagnosis and intervention are important for successful treatment of dogs with chronic hepatitis because patients with end-stage disease and signs of decompensated liver function have a poorer prognosis.

IN SUMMARY

There is still much unknown about the etiology and treatment of chronic hepatitis in dogs. The World Small Animal Veterinary Association guidelines1 provide an important scaffolding of the etiology and treatment of this disease that should build on our current knowledge and facilitate multicenter studies, with the hope of improving patient survival and outcome.

aPTT = activated partial thromboplastin time; BMBT = buccal mucosal bleeding time; BUN = blood urea nitrogen; PT = prothrombin time

Yuri LawrenceYuri Lawrence, DVM, MA, MS, Diplomate ACVIM, is enrolled in the Texas A&M University Gastrointestinal PhD program and also serves as a senior clinician at the institution’s small animal hospital. Dr. Lawrence received his DVM from Tufts University; then completed an MA in anatomy and neurobiology at Boston University, an internship in small animal medicine and surgery at North Carolina State University, and a residency in small animal internal medicine and MS in veterinary science at Oregon State University.

 

Jorg SteinerJörg Steiner, MedVet, DrMedVet, PhD, AGAF, Diplomate ACVIM and ECVIM, is a professor in the Departments of Small Animal Medicine and Surgery, and Veterinary Pathobiology, as well as the director of the Gastrointestinal Laboratory, at Texas A&M University. He was recognized as a Fellow of the American Gastroenterology Association. He received his veterinary degrees from Ludwig-Maximilians University, Munich, Germany; then completed an internship at University of Pennsylvania, residency in small animal internal medicine at Purdue University, and his PhD at Texas A&M University.

 

References

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  2. Poldervaart JH, Favier RP, Penning LC, et al. Primary hepatitis in dogs: A retrospective review (2002-2006). J Vet Intern Med 2009; 23:72-80.
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  12. Gomez Selgas A, Bexfield N, Scase TJ, et al. Total serum bilirubin as a negative prognostic factor in idiopathic canine chronic hepatitis. J Vet Diagn Invest 2014; 26:246-251.
  13. Center SA. Chronic hepatitis, cirrhosis, breed-specific hepatopathies, copper storage hepatopathy, suppurative hepatitis, granulomatous hepatitis, and idiopathic hepatic fibrosis. In Guilford WG, Center SA, Strombeck D (eds): Strombeck’s Small Animal Gastroenterology, 3rd ed. Philadephia: Saunders, 1996.
  14. Levien AS, Weisse C, Donovan TA, et al. Assessment of the efficacy and potential complications of transjugular liver biopsy in canine cadavers. J Vet Intern Med 2014; 28:338-345.
  15. Kemp SD, Zimmerman KL, Panciera DL, et al. A comparison of liver sampling techniques in dogs. J Vet Intern Med 2014 [epub ahead of print].
  16. Boisclair J, Dore M, Beauchamp G, et al. Characterization of the inflammatory infiltrate in canine chronic hepatitis. Vet Pathol 2001; 38:628-635.
  17. Bataller R, Brenner DA. Hepatic stellate cells as a target for the treatment of liver fibrosis. Semin Liver Dis 2001; 21:437-451.
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  19. Favier RP, Poldervaart JH, van den Ingh TS, et al. A retrospective study of oral prednisolone treatment in canine chronic hepatitis. Vet Q 2013; 33:113-120.
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  21. Chiou YL, Chen YH, Ke T, et al. The effect of increased oxidative stress and ferritin in reducing the effectiveness of therapy in chronic hepatitis C patients. Clin Biochem 2012; 45:1389-1393.
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  24. Venturini D, Simao AN, Barbosa DS, et al. Increased oxidative stress, decreased total antioxidant capacity, and iron overload in untreated patients with chronic hepatitis C. Dig Dis Sci 2010; 55:1120-1127.
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for='input_6_10_1' id='input_6_10_1_label' >Street Address</label> </span><span class='ginput_full address_line_2' id='input_6_10_2_container' > <input type='text' name='input_10.2' id='input_6_10_2' value='' /> <label for='input_6_10_2' id='input_6_10_2_label' >Address Line 2</label> </span><span class='ginput_left address_city' id='input_6_10_3_container' > <input type='text' name='input_10.3' id='input_6_10_3' value='' aria-required="true"/> <label for='input_6_10_3' id='input_6_10_3_label' >City</label> </span><span class='ginput_right address_state' id='input_6_10_4_container' > <input type='text' name='input_10.4' id='input_6_10_4' value='' aria-required="true"/> <label for='input_6_10_4' id='input_6_10_4_label' >State / Province / Region</label> </span><span class='ginput_left address_zip' id='input_6_10_5_container' > <input type='text' name='input_10.5' id='input_6_10_5' value='' aria-required="true"/> <label for='input_6_10_5' id='input_6_10_5_label' >ZIP / Postal Code</label> </span><span class='ginput_right address_country' id='input_6_10_6_container' > <select name='input_10.6' id='input_6_10_6' aria-required="true"><option value='' selected='selected'></option><option value='Afghanistan' >Afghanistan</option><option value='Åland Islands' >Åland Islands</option><option value='Albania' >Albania</option><option value='Algeria' >Algeria</option><option value='American Samoa' >American Samoa</option><option value='Andorra' >Andorra</option><option value='Angola' >Angola</option><option value='Anguilla' >Anguilla</option><option value='Antarctica' >Antarctica</option><option value='Antigua and Barbuda' >Antigua and Barbuda</option><option value='Argentina' >Argentina</option><option value='Armenia' >Armenia</option><option value='Aruba' >Aruba</option><option value='Australia' >Australia</option><option value='Austria' >Austria</option><option value='Azerbaijan' >Azerbaijan</option><option value='Bahamas' >Bahamas</option><option value='Bahrain' >Bahrain</option><option value='Bangladesh' >Bangladesh</option><option value='Barbados' >Barbados</option><option value='Belarus' >Belarus</option><option value='Belgium' >Belgium</option><option value='Belize' >Belize</option><option value='Benin' >Benin</option><option value='Bermuda' >Bermuda</option><option value='Bhutan' >Bhutan</option><option value='Bolivia' >Bolivia</option><option value='Bonaire, Sint Eustatius and Saba' >Bonaire, Sint Eustatius and Saba</option><option value='Bosnia and Herzegovina' >Bosnia and Herzegovina</option><option value='Botswana' >Botswana</option><option value='Bouvet Island' >Bouvet Island</option><option value='Brazil' >Brazil</option><option value='British Indian Ocean Territory' >British Indian Ocean Territory</option><option value='Brunei Darussalam' >Brunei Darussalam</option><option value='Bulgaria' >Bulgaria</option><option value='Burkina Faso' >Burkina Faso</option><option value='Burundi' >Burundi</option><option value='Cambodia' >Cambodia</option><option value='Cameroon' >Cameroon</option><option value='Canada' >Canada</option><option value='Cape Verde' >Cape Verde</option><option value='Cayman Islands' >Cayman Islands</option><option value='Central African Republic' >Central African Republic</option><option value='Chad' >Chad</option><option value='Chile' >Chile</option><option value='China' >China</option><option value='Christmas Island' >Christmas Island</option><option value='Cocos Islands' >Cocos Islands</option><option value='Colombia' >Colombia</option><option value='Comoros' >Comoros</option><option value='Congo, Democratic Republic of the' >Congo, Democratic Republic of the</option><option value='Congo, Republic of the' >Congo, Republic of the</option><option value='Cook Islands' >Cook Islands</option><option value='Costa Rica' >Costa Rica</option><option value='Côte d&#039;Ivoire' >Côte d&#039;Ivoire</option><option value='Croatia' >Croatia</option><option value='Cuba' >Cuba</option><option value='Curaçao' >Curaçao</option><option value='Cyprus' >Cyprus</option><option value='Czech Republic' >Czech Republic</option><option value='Denmark' >Denmark</option><option value='Djibouti' >Djibouti</option><option value='Dominica' >Dominica</option><option value='Dominican Republic' >Dominican Republic</option><option value='Ecuador' >Ecuador</option><option value='Egypt' >Egypt</option><option value='El Salvador' >El Salvador</option><option value='Equatorial Guinea' >Equatorial Guinea</option><option value='Eritrea' >Eritrea</option><option value='Estonia' >Estonia</option><option value='Eswatini (Swaziland)' >Eswatini (Swaziland)</option><option value='Ethiopia' >Ethiopia</option><option value='Falkland Islands' >Falkland Islands</option><option value='Faroe Islands' >Faroe Islands</option><option value='Fiji' >Fiji</option><option value='Finland' >Finland</option><option value='France' >France</option><option value='French Guiana' >French Guiana</option><option value='French Polynesia' >French Polynesia</option><option value='French Southern Territories' >French Southern Territories</option><option value='Gabon' >Gabon</option><option value='Gambia' >Gambia</option><option value='Georgia' >Georgia</option><option value='Germany' >Germany</option><option value='Ghana' >Ghana</option><option value='Gibraltar' >Gibraltar</option><option value='Greece' >Greece</option><option value='Greenland' >Greenland</option><option value='Grenada' >Grenada</option><option value='Guadeloupe' >Guadeloupe</option><option value='Guam' >Guam</option><option value='Guatemala' >Guatemala</option><option value='Guernsey' >Guernsey</option><option value='Guinea' >Guinea</option><option value='Guinea-Bissau' >Guinea-Bissau</option><option value='Guyana' >Guyana</option><option value='Haiti' >Haiti</option><option value='Heard and McDonald Islands' >Heard and McDonald Islands</option><option value='Holy See' >Holy See</option><option value='Honduras' >Honduras</option><option value='Hong Kong' >Hong Kong</option><option value='Hungary' >Hungary</option><option value='Iceland' >Iceland</option><option value='India' >India</option><option value='Indonesia' >Indonesia</option><option value='Iran' >Iran</option><option value='Iraq' >Iraq</option><option value='Ireland' >Ireland</option><option value='Isle of Man' >Isle of Man</option><option value='Israel' >Israel</option><option value='Italy' >Italy</option><option value='Jamaica' >Jamaica</option><option value='Japan' >Japan</option><option value='Jersey' >Jersey</option><option value='Jordan' >Jordan</option><option value='Kazakhstan' >Kazakhstan</option><option value='Kenya' >Kenya</option><option value='Kiribati' >Kiribati</option><option value='Kuwait' >Kuwait</option><option value='Kyrgyzstan' >Kyrgyzstan</option><option value='Lao People&#039;s Democratic Republic' >Lao People&#039;s Democratic Republic</option><option value='Latvia' >Latvia</option><option value='Lebanon' >Lebanon</option><option value='Lesotho' >Lesotho</option><option value='Liberia' >Liberia</option><option value='Libya' >Libya</option><option value='Liechtenstein' >Liechtenstein</option><option value='Lithuania' >Lithuania</option><option value='Luxembourg' >Luxembourg</option><option value='Macau' >Macau</option><option value='Macedonia' >Macedonia</option><option value='Madagascar' >Madagascar</option><option value='Malawi' >Malawi</option><option value='Malaysia' >Malaysia</option><option value='Maldives' >Maldives</option><option value='Mali' >Mali</option><option value='Malta' >Malta</option><option value='Marshall Islands' >Marshall Islands</option><option value='Martinique' >Martinique</option><option value='Mauritania' >Mauritania</option><option value='Mauritius' >Mauritius</option><option value='Mayotte' >Mayotte</option><option value='Mexico' >Mexico</option><option value='Micronesia' >Micronesia</option><option value='Moldova' >Moldova</option><option value='Monaco' >Monaco</option><option value='Mongolia' >Mongolia</option><option value='Montenegro' >Montenegro</option><option value='Montserrat' >Montserrat</option><option value='Morocco' >Morocco</option><option value='Mozambique' >Mozambique</option><option value='Myanmar' >Myanmar</option><option value='Namibia' >Namibia</option><option value='Nauru' >Nauru</option><option value='Nepal' >Nepal</option><option value='Netherlands' >Netherlands</option><option value='New Caledonia' >New Caledonia</option><option value='New Zealand' >New Zealand</option><option value='Nicaragua' >Nicaragua</option><option value='Niger' >Niger</option><option value='Nigeria' >Nigeria</option><option value='Niue' >Niue</option><option value='Norfolk Island' >Norfolk Island</option><option value='North Korea' >North Korea</option><option value='Northern Mariana Islands' >Northern Mariana Islands</option><option value='Norway' >Norway</option><option value='Oman' >Oman</option><option value='Pakistan' >Pakistan</option><option value='Palau' >Palau</option><option value='Palestine, State of' >Palestine, State of</option><option value='Panama' >Panama</option><option value='Papua New Guinea' >Papua New Guinea</option><option value='Paraguay' >Paraguay</option><option value='Peru' >Peru</option><option value='Philippines' >Philippines</option><option value='Pitcairn' >Pitcairn</option><option value='Poland' >Poland</option><option value='Portugal' >Portugal</option><option value='Puerto Rico' >Puerto Rico</option><option value='Qatar' >Qatar</option><option value='Réunion' >Réunion</option><option value='Romania' >Romania</option><option value='Russia' >Russia</option><option value='Rwanda' >Rwanda</option><option value='Saint Barthélemy' >Saint Barthélemy</option><option value='Saint Helena' >Saint Helena</option><option value='Saint Kitts and Nevis' >Saint Kitts and Nevis</option><option value='Saint Lucia' >Saint Lucia</option><option value='Saint Martin' >Saint Martin</option><option value='Saint Pierre and Miquelon' >Saint Pierre and Miquelon</option><option value='Saint Vincent and the Grenadines' >Saint Vincent and the Grenadines</option><option value='Samoa' >Samoa</option><option value='San Marino' >San Marino</option><option value='Sao Tome and Principe' >Sao Tome and Principe</option><option value='Saudi Arabia' >Saudi Arabia</option><option value='Senegal' >Senegal</option><option value='Serbia' >Serbia</option><option value='Seychelles' >Seychelles</option><option value='Sierra Leone' >Sierra Leone</option><option value='Singapore' >Singapore</option><option value='Sint Maarten' >Sint Maarten</option><option value='Slovakia' >Slovakia</option><option value='Slovenia' >Slovenia</option><option value='Solomon Islands' >Solomon Islands</option><option value='Somalia' >Somalia</option><option value='South Africa' >South Africa</option><option value='South Georgia' >South Georgia</option><option value='South Korea' >South Korea</option><option value='South Sudan' >South Sudan</option><option value='Spain' >Spain</option><option value='Sri Lanka' >Sri Lanka</option><option value='Sudan' >Sudan</option><option value='Suriname' >Suriname</option><option value='Svalbard and Jan Mayen Islands' >Svalbard and Jan Mayen Islands</option><option value='Sweden' >Sweden</option><option value='Switzerland' >Switzerland</option><option value='Syria' >Syria</option><option value='Taiwan' >Taiwan</option><option value='Tajikistan' >Tajikistan</option><option value='Tanzania' >Tanzania</option><option value='Thailand' >Thailand</option><option value='Timor-Leste' >Timor-Leste</option><option value='Togo' >Togo</option><option value='Tokelau' >Tokelau</option><option value='Tonga' >Tonga</option><option value='Trinidad and Tobago' >Trinidad and Tobago</option><option value='Tunisia' >Tunisia</option><option value='Turkey' >Turkey</option><option value='Turkmenistan' >Turkmenistan</option><option value='Turks and Caicos Islands' >Turks and Caicos Islands</option><option value='Tuvalu' >Tuvalu</option><option value='Uganda' >Uganda</option><option value='Ukraine' >Ukraine</option><option value='United Arab Emirates' >United Arab Emirates</option><option value='United Kingdom' >United Kingdom</option><option value='United States' >United States</option><option value='Uruguay' >Uruguay</option><option value='US Minor Outlying Islands' >US Minor Outlying Islands</option><option value='Uzbekistan' >Uzbekistan</option><option value='Vanuatu' >Vanuatu</option><option value='Venezuela' >Venezuela</option><option value='Vietnam' >Vietnam</option><option value='Virgin Islands, British' >Virgin Islands, British</option><option value='Virgin Islands, U.S.' >Virgin Islands, U.S.</option><option value='Wallis and Futuna' >Wallis and Futuna</option><option value='Western Sahara' >Western Sahara</option><option value='Yemen' >Yemen</option><option value='Zambia' >Zambia</option><option value='Zimbabwe' >Zimbabwe</option></select> <label for='input_6_10_6' id='input_6_10_6_label' 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