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Basics ⬇

Basics

Definition

  • Hepatic fibrosis-replacement/effacement of hepatic parenchyma, intrasinusoidal, variable zonal, deposition of extracellular matrix (ECM).
  • Cirrhosis-regenerative nodules with dissecting fibrotic partitions and regions of parenchymal extinction, deranging hepatic architecture; usually reflects chronic necro-inflammatory liver injury.

Pathophysiology

  • Fibrosis-usually reflects injury associated release of cytokines /mediators stimulating production and accumulation of ECM; exception: ductal plate malformation (DPM)-with congenital hepatic fibrosis [CHF] phenotype (severe portal-to-portal bridging fibrosis without chronic inflammation).
  • Cirrhosis-consequence of chronic hepatic injury, fibrogenesis, and hepatic regeneration; typified by: regenerative nodules, reduced functional hepatic mass, collagen deposition in sinusoids (space of Disse) or portal tracts, compromising parenchymal perfusion.
  • Cirrhosis/fibrosis-lead to hepatic dysfunction, capillarization of hepatic sinusoids, collagenization of the space of Disse, development of sinusoidal hypertension, intrahepatic shunting through collagenized sinusoids and recanalized vascular pathways in fibrotic partitions between regenerative nodules. These microcirculatory disturbances impair exchanges between blood and hepatocytes.
  • Sinusoidal hypertension-leads to (1) hepatofugal portal flow (away from liver), (2) splanchnic hypertension, (3) APSS formation, (4), episodic HE, (5) splanchnic pooling of blood, decreased effective systemic blood volume, stimulation of renal sodium and water retention, with ascites formation, (6) hypertensive splanchnic vasculopathy predisposing to enteric bleeding.

Systems Affected

  • GI-splanchnic portal hypertension leads to ascites and propensity for enteric bleeding.
  • Neurologic-HE.
  • Hemic-RBC microcytosis reflect APSS; bleeding tendencies: failed factor synthesis or activation, thrombocytopenia; reduced anticoagulants increase risk for thrombosis.
  • Renal/urologic-ammonium biurate crystalluria; isosthenuria: PU/PD; hepatorenal syndrome (rare) may follow therapeutic paracentesis of large volume ascites (Postcentesis Hypotension Syndrome [PHS]).
  • Endocrine/metabolic-hypoglycemia if end-stage liver failure, usually provoked by prolonged inappetence.
  • Respiratory-tachypnea if tense ascites; bicavity effusion (rare, leakage across diaphragm (rare), pulmonary edema (rare).
  • Skin-superficial necrolytic dermatitis (see Diabetic Hepatopathy), unkempt coat.

Genetics

Familial predisposition for chronic hepatitis-Doberman pinscher, cocker spaniel, Labrador retriever, Maltese, Bedlington terrier (copper related), others.

Incidence/Prevalence

High in dogs with chronic necroinflammatory liver disease, animals with chronic EHBDO, dogs with severe hepatic copper accumulation.

Signalment

Species

  • Cirrhosis: dogs with chronic hepatitis; cats with chronic cholangitis/cholangiohepatitis; dogs and cats with chronic EHBDO.
  • Severe fibrosis: dogs and cats with severe DPM-CHF phenotype.

Breed Predilection

  • Many breeds and mixed breed dogs.
  • Copper-associated hepatopathy (Cu-AH-genetics proven only in Bedlington terriers; Labrador retrievers, Doberman pinschers and Dalmatians appear predisposed, but all breeds at risk for Cu-AH due to dietary Cu intake.
  • DPM-CHF phenotype; boxers may be predisposed, many breeds of dogs and cats; cats with polycystic malformations at risk.

Mean Age and Range

  • Cirrhosis (dogs)-any age; more common in middle to older dogs; Cu-AH any age.
  • Biliary cirrhosis (cats)-with chronic cholangiohepatitis often >7 years old.
  • Fibrosis-DPM-CHF phenotype (dogs, cats): ECM accumulates with aging (suspected), genetic cause (see Ductal Plate Malformations).

Predominant Gender

  • Cocker spaniels-may be higher in males.
  • Doberman pinschers and Labrador retrievers-no sex predilection.
  • DPM: no gender predilections.

Signs

General Comments

  • Initially-vague and nonspecific.
  • Later-relate to complications of portal hypertension (e.g., HE, ascites, gastroduodenal bleeding), and impaired hepatic function.

Historical Findings

  • Chronic intermittent lethargy, anorexia, reduced body condition
  • GI signs: vomiting, diarrhea or constipation
  • Melena: late stage or as develop APSS
  • PU/PD
  • Late onset-ascites, bleeding, HE
  • Jaundice: acquired necroinflammatory disease often jaundiced. DPM usually anicteric
  • Cats-ascites uncommon with acquired necroinflammatory disease, more common with DPM; ptyalism, aggression, seizures with HE.

Physical Examination Findings

  • Lethargy
  • Poor body condition/coat
  • ± Variable jaundice
  • ± Ascites
  • ± HE
  • Obstructive uropathy: ammonium biurates
  • Anasarca-rare; may develop with overzealous fluid therapy
  • Liver size-dogs microhepatia, cats variable
  • Coagulopathy: variable, uncommon in DPM
  • Cutaneous lesions: superficial necrolytic dermatitis (severe degenerative vacuolar hepatopathy; see Diabetic Hepatopathy).

Causes

  • Chronic necroinflammatory, oxidant, or immune-mediated liver injury has many causes. May develop subsequent to chronic inflammatory bowel disease or pancreatitis.
  • Cu-AH.
  • Drug- or toxin-induced liver injury-anticonvulsants; azole antifungals; NSAIDs oxibendazole; trimethoprim-sulfamethoxazole; chronic food-borne toxins (aflatoxins), others.
  • Infections-leptospirosis, canine adenovirus I.
  • Chronic cholangiohepatitis (cats).
  • Chronic EHBDO (>6 weeks, dogs and cats).
  • Single episode of massive hepatic necrosis; sago palm (cycad toxicity), xylitol, NSAIDs in dogs with substantial Cu accumulation.

Risk Factors

  • Breed predisposition: Cu-AH or other causes yet ill-defined (see above)
  • Dietary Cu intake > patient tolerance
  • Hepatic iron accumulation: supplementation
  • Chronic hepatobiliary inflammation
  • Chronic EHBDO
  • Chronic phenobarbital administration (dogs)
  • NSAIDS: (dogs), especially carprofen

Diagnosis ⬆ ⬇

Diagnosis

Differential Diagnosis

  • Chronic hepatitis-common in dogs
  • Cholangiohepatitis-common in cats
  • Noncirrhotic portal hypertension: dogs
  • Chronic EHBDO-dogs, cats
  • Chronic IBD or pancreatitis-dogs, cats
  • Hepatic neoplasia
  • Metastatic neoplasia or carcinomatosis
  • Congenital portosystemic vascular anomaly (PSVA, shunt)
  • Congenital portal atresia: intrahepatic or extrahepatic
  • Right-sided heart failure, pericardial disease
  • Cats-hepatic lipidosis; FIP; toxoplasmosis
  • Hemolytic anemia (jaundice differential)

CBC/Biochemistry/Urinalysis

CBC

  • Microcytic RBCs: APSS; mild anemia: small RBCs with normal cell count; anemia of chronic disease; microangiopathic shearing: sinusoidal fibrosis, APSS.
  • Mild thrombocytopenia, variable.
  • Leukogram: variable.

Biochemistry

  • Bilirubin variable.
  • Liver enzyme activities-high (ALT > ALP) noted before clinical signs or liver dysfunction; at end-stage enzymes may decline.
  • Normal to hypoalbuminemia.
  • Normal to hyperglobulinemia.
  • Hypocholesterolemia-reflects APSS.
  • Low BUN-reduced urea cycle activity, APSS, protein-restricted diet, PU/PD.
  • Hypoglycemia-rare in dogs, rare in cats.
  • Hypokalemia-may predispose to HE.
  • Hyponatremia-fluid imbalance with ascites.

Urinalysis

  • Isosthenuria-with PU/PD
  • Ammonium biurate crystalluria
  • Bilirubinuria, bilirubin crystalluria

Other Laboratory Tests

  • Ascitic fluid-pure or modified transudate
  • Coagulation tests-inconsistently prolonged PT, APTT, buccal mucosal bleeding time
  • Low protein C and antithrombin activity-reflects APSS, synthetic failure, or DIC
  • Serum bile acids-high; reflects APSS or cholestasis in cirrhosis
  • Hyperammonemia: inferred from ammonium biurate crystalluria

Imaging

Radiography

Abdominal-small to normal sized liver; ascites may obscure details; urate calculi radiolucent unless calcium complexed.

Ultrasonography

  • Abdominal-hyperechoic or mixed echogenic parenchyma; ± nodularity; abdominal effusion (ascites); APSS (color flow Doppler); or no parenchymal change in some cases.
  • Doppler interrogation of portal vasculature-may confirm hepatofugal flow or nests of APSS especially near left kidney or splenic vessels.

Diagnostic Procedures

  • Fine-needle aspiration cytology-helps rule out neoplasia; rule-in bacterial infection; cannot define fibrosis or nonsuppurative inflammation.
  • Liver biopsy-for definitive diagnosis; 18G needle core too small for accuracy; use 14-16G.
  • Laparoscopy-best biopsy method; permits gross visualization, documents APSS, biopsy access to multiple liver lobes and focal lesions.

Pathologic Findings

Gross

  • Fibrosis-small, firm irregular to finely nodular liver; DPM-CHF may not be small; fibrotic liver may display APSS, ± ascites.
  • Cirrhosis-firm irregular liver; prominent micro- or macro-nodules, APSS, ± ascites.

Histopathology

  • Immune-mediated hepatitis-periportal, lobular, or centrilobular lymphoplasmacytic infiltrates, hepatic cord disorganization, sinusoidal fibrosis (space of Disse), biliary hyperplasia (ductular reaction).
  • Cu-AH-initially centrilobular, may evolve immune-mediated hepatitis; single necrotic hepatocytes.
  • DPM-bridging partitions with proliferative nonfunctional embryonic bile ducts embedded in ECM interconnecting portal regions.
  • Post-necrotic fibrosis-fibrosis marks regenerative repair, disorganized wide hepatic cords, engorged lymphatics reflect sinusoidal hypertension.
  • Cirrhosis-diffuse lesion; fibrosis, nodular regeneration distorting lobular architecture (double-wide hepatic cord, 1 cell width = normal), periportal or sinusoidal fibrosis depending on zone of chronic injury, engorged lymphatics reflect sinusoidal hypertension; single hepatocyte necrosis if active disease.

Treatment ⬆ ⬇

Treatment

Appropriate Health Care

  • Outpatient-minimally symptomatic patients.
  • Inpatient-diagnostic tests; treatment for dehydration, severe HE, enteric bleeding (hypertensive vasculopathy), tense ascites.

Nursing Care

  • Fluids-avoid lactate if hepatic failure; avoid sodium loading if ascites.
  • B complex vitamins (esp. cats)-2 mL/L fluid advised.
  • Vitamin K1-0.5–1.5 mg/kg SC q12h for 3 doses initially; titrate with PIVKA or PT.
  • Glucose-if hypoglycemia; 2.5–5% dextrose in polyionic solution; titrate to response.
  • Potassium chloride-in fluids, as needed.
  • Avoid alkalosis-worsens HE.
  • Therapeutic large volume abdominocentesis if tense ascites is non-responsive to medical treatment; caution: PHS-hypotensive crisis and acute renal failure (IV volume shifts).

Activity

Limit

Diet

  • Withhold oral food in acute severe HE if stupor, coma, or vomiting associated with enteric bleeding or pancreatitis.
  • Consider PPN or TPN.
  • If HE: restrict protein intake, use soy or dairy protein sources (dogs) combined with medical interventions to increase nitrogen tolerance; individualize protein intake to maintain body condition, muscle mass, albumin (see Hepatic Encephalopathy).
  • Sodium restriction if ascites.
  • Fat restriction rarely needed.
  • Supplement water-soluble vitamins.

Client Education

  • Treatment is palliative and symptomatic.
  • Antifibrotics may reduce fibrosis but limited evidence; fibrosis diminished by control of inflammation and provocative diseases.
  • Attenuate factors provoking HE-azotemia, dehydration; infection; catabolism; high protein meals, hypokalemia; alkalemia; constipation, endoparasitism; enteric bleeding; certain drugs.

Surgical Considerations

  • Cirrhosis-high anesthetic risk; gas anesthesia preferred-isoflurane or sevoflurane.
  • Coagulopathy-predisposes to bleeding with minor invasive procedures/surgeries; BMBT may better assess risk for bleeding.
  • Postoperative intensive care-avoid HE, maintain hydration, euglycemia, electrolytes, acid-base balance (avoid alkalemia).
  • Predisposed to enteric bacterial translocation-judiciously administer antibiotics esp. if surgical procedures involve alimentary canal or biliary structures.

Medications ⬆ ⬇

Medications

Drug(s) Of Choice

  • Treatments for specific etiologies: chelate Cu if Cu-AH); withdraw potentially hepatotoxic drugs, herbal or natural remedies.
  • No clinical trials prove efficacy of specific regimens in animals.

Immune Modulation-see Hepatitis, Chronic

  • Prednisolone/prednisone-1–4 mg/kg q24h PO; taper to lowest effective dose (e.g., 0.25–0.5 mg/kg PO q48h); reduce dose with polypharmacy; survival effect see reference.
  • Azathioprine-dogs: 1–2 mg/kg PO q48h; use 3-day loading SID dose; contraindicated in cats (toxic); dogs: combined with prednisone, antioxidants, antifibrotics PPC, or cyclosporine.

Antifibrotics-see Hepatitis, Chronic

  • Immunomodulation, SAMe, silibinin, Vit. E: also considered antifibrotics-interfere in signaling processes that promote fibrogenesis.
  • Ursodiol-7.5 mg/kg/day PO q12h with food: use indefinitely; provides hepatoprotectant, antiinflammatory, choleretic, antioxidant, and other benefits.
  • Polyunsaturated phosphatidylcholine with dilinolylphosphatidylcholine (PhosChol)-25 mg/kg/q24h, mix with food. No side effects.
  • Colchicine-0.025–0.03 mg/kg q24–48h: no evidence supporting chronic benefit; side effects complicate use: inhibits mitosis-cell replication, may cause GI, bone marrow, neurologic adverse effects, avoid concurrent p450 cytochrome inhibition (e.g., ketoconazole).
  • Losartan and telmisartan-losartan: 0.5 mg/kg/q24h or telmisartan: 0.5–1 mg/kg q24h for initial dosing, closely monitor blood pressure, renal function, and potassium, reducing dose if hypotension or hyperkalemia. These are angiotensin receptor blockers (ARB), selectively antagonizing angiotensin-1 receptor, bypassing intermediary activation steps within the RAAS cascade. Angiotensin-2 acting via angiotensin-1 (AT1) receptors on hepatic stellate cells (HSC) is a key mediator of hepatic sinusoidal fibrosis, increasing HSC proliferation and HSC synthesis of growth factors, cytokines, and additional bioactive molecules. Evidence suggests that AT1 receptor blockade reduces HSC activation, and attenuates liver fibrosis, but may impose a suppressive influence on hepatic regeneration (evidence supports HSC activation is highly connected to hepatocyte proliferation and differentiation). These drugs also increase PPARγ expression associated with induced HSC quiescence. ARBs are used in humans as antihypertensives with partial PPAR-γ agonist activity; and shown have nephroprotective (diabetes, renal injury models), to protect against some forms of drug-induced hepatotoxicity, and to limit hepatic fibrosis in various chronic models of liver disease (e.g., chronic EHBDO, Schistosomiasis induced fibrosis, CCl4 induced injury, others).

Antioxidants

  • Necroinflammatory disorders.
  • S-adenosylmethionine (SAMe, use bioavailable product as proven GSH donor)-20 mg/kg q24h PO, empty stomach. Vitamin E mixed tocopherols-10 U/kg q24h PO with food.

Hepatoprotectants

  • Necroinflammatory disorders.
  • Ursodeoxycholate, Vitamin E, SAMe also provide hepatoprotectant effects.
  • Silibinin-efficacy unclear, use PPC complexed form (bioavailable), 2–5 mg/kg q24h PO.
  • Elemental zinc: 1.5–3 mg PO q24h (if low liver zinc confirmed); adjust dose with plasma zinc measurements; avoid 800 µg/dL.

Gastroprotectants

Gastric acid inhibitors-if enteric bleeding (see Hepatitis, Chronic).

  • Eliminate endoparasitism.

Specific Conditions

Ascites

  • Restrict activity and sodium intake combined with diuretic therapy.
  • Dietary sodium restriction (0.2% dry matter basis or <100 mg/100 kcal).
  • Diuretics (see Hypertension, Portal; Hepatitis, Chronic); slowly mobilize effusion: furosemide (0.5–2 mg/kg IV, SC, PO q12h) combined with spironolactone (0.5–2 mg/kg PO q12h); adjust dose to response (4–7 day recheck observation); individualize chronic treatment to response; diuretics may be intermittently used to mobilize recurrent ascites.
  • Therapeutic large volume abdominocentesis if nonresponsive ascites mobilization after 7–14 days of diuretics and sodium restriction; may require fluid support as a result of intravascular to abdominal fluid shift causing PHS and ARF.
  • Consider vasopressin V2 antagonists with low dose diuretics for treatment resistant ascites (no published data for dogs or cats); tolvaptan at 10 mg/kg used in dogs with experimentally modeled congestive heart failure.

Coagulopathy

See Coagulopathy of Liver Disease

HE

See Hepatic Encephalopathy

Contraindications

NSAIDs-avoid; potentiate enteric bleeding; may worsen ascites; potentiates centrilobular hepatic necrosis-hepatotoxic metabolites and Cu-AH.

Precautions

  • Diuretics-dehydration, hypokalemia, alkalemia worsen HE.
  • Glucocorticoids-increase susceptibility to infection, enteric bleeding, sodium and water retention and ascites, protein catabolism, HE.
  • Avoid drugs or reduce dose if first-pass hepatic extraction, if require hepatic conjugation or biotransformation (e.g., metronidazole-reduce conventional dose to 7.5 mg/kg PO q12h, as used for HE).

Alternative Drug(s)

  • Dexamethasone-if ascites, replace prednisone/prednisolone to avoid mineralo-corticoid effect); divide pred. dose by 7–10, administer q3–4 days; taper dose to efficacy.
  • Mycophenolate: alternative for azathioprine.

Follow-Up ⬆ ⬇

Follow-Up

Patient Monitoring

  • Liver enzymes, albumin, BUN, cholesterol, bilirubin-monthly to quarterly, as needed.
  • Serial monitoring of TSBA-does not add prognostic or diagnostic information.
  • Body condition score, weight, muscle mass-reflects nutritional adequacy/nitrogen balance.
  • Abdominal girth: reflects ascites volume.
  • Azathioprine, mycophenolate, colchicine-monitor for possible bone marrow toxicity (serial CBCs) and other side effects.

Possible Complications

HE, septicemia, bleeding-may be life-threatening; DIC-may be a terminal event.

Expected Course and Prognosis

  • Occasional flare-ups of HE and ascites may require hospitalizations for adjustment of nutritional and medical interventions.
  • Sodium restriction and diuretics may require titration to achieve optimal control of ascites.
  • Natural history of fibrotic/cirrhotic hepatic disease in dogs is poorly characterized.
  • Presence of ascites indicates severe disease.
  • DPM-survival up to 12 years after diagnosis.
  • Cirrhosis-survival >5 years with careful interventional management.

Miscellaneous ⬆

Miscellaneous

Zoonotic Potential

Dogs with leptospirosis-associated chronic liver disease (rare) may shed organisms.

Abbreviations

  • ACT = activated clotting time
  • APSS = acquired portosystemic shunt(s)
  • APTT = activated partial thromboplastin time
  • ARF = acute renal failure
  • Cu = copper
  • ECM = extracellular matrix
  • EHBDO = extrahepatic bile duct occlusion
  • HE = hepatic encephalopathy
  • IV = intravascular
  • PHS = postcentesis hypotension syndrome
  • PIVKA = proteins invoked by vitamin K absence or antagonism
  • PPC = polyenylphosphatidylcholine
  • PPN = partial parenteral nutrition
  • PT = prothrombin time
  • TPN = total parenteral nutrition

Suggested Reading

Center SA. Metabolic, antioxidant, nutraceutical, probiotic, and herbal therapies relating to the management of hepatobiliary disorders. Vet Clin North Am Small Anim Pract 2004, 34:67–172.

Raffan E, McCallum A, Scase TJ. Ascites is a negative prognostic indicator in chronic hepatitis in dogs. J Vet Intern Med 2009, 23:63–66.

Strombeck DR, et al. Effects of corticosteroid treatment on survival time in dogs with chronic hepatitis: 151 cases (1977–1985). J Am Vet Med Assoc 1988, 193:1109–1113.

Author Sharon A. Center

Consulting Editor Sharon A. Center

Client Education Handout Available Online