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Basics ⬇

Basics

Definition

  • Ductal plate malformations (DPMs) are noninflammatory hepatopathies recognized in juvenile and young adult dogs or cats reflecting developmental abnormalities of biliary structures.
  • Diverse phenotypes defined by involved structures, coexistent hepatic fibrosis, portal hypertension, and acquired portosystemic shunts (APSS).
  • Propensity for septic suppurative cholangitis, choledochitis, cholelithiasis, or extrahepatic bile duct obstruction (EHBDO) reflects structural malformations.
  • Represent abnormal development, differentiation, and resorption of embryonic anlage of the ductal plate, the embryologic precursor of the portal tract and bile ducts.
  • In humans (and knockout mouse models), DPMs represent gene mutations influencing structure or function of primary cilia.
  • Primary cilia-solitary, non-motile organelles located on the apical surface of most mammalian cells. These function as mechano-, osmo-, and chemoreceptors and are involved in designation of planar cell polarity, in cell cycle control, and numerous additional signaling pathways. Pathomechanisms leading to DPM involves interrupted tubulogenesis.
  • Polycystic kidney disease in Persian cats involves the polycystin-1 precursor gene; ∼ 15% develop hepatic DPM.

Four Major DPM Phenotypes

  • Choledochal cyst-diverticulum protruding from the common bile duct (CBD) or cystic duct; has propensity for infection-similar to appendicitis in humans causing sepsis, EHBDO, and cranial abdominal mass effect.
  • Caroli's malformation-irregular sacculation and dilation of hepatic, interlobular and large intralobular bile ducts; ducts have variable morphology appearing elongate, irregular, lanceolate, or sacculated, usually with attenuated biliary epithelium and intraluminal debris; with chronicity may develop choleliths, dystrophic mineralization, and septic cholangitis.
  • Diffuse intralobular bile duct malformation without OR with diffuse portal-to-portal bridging fibrosis; if fibrosis = congenital hepatic fibrosis (CHF)-Abnormal tubulogenesis of small intralobular bile ducts reflect abnormal resorption of extraneous ductule anlage; results in retention of numerous small malformed proliferative ductules lacking luminal apertures, variously embedded in excessive extracellular matrix (ECM); amalgamation of proliferative ductules, numerous stout arterials, and ECM dimensionally expand portal tracts forming variable bridging partitions between portal regions; portal veins are often inconspicuous; dense fibrosis may cause presinusoidal portal hypertension and formation of APSS in CHF phenotype.
  • von Meyenberg complexes (VMC)-isolated single microscopic DPM comprised of clusters of proliferative intralobular bile ductule profiles embedded in an expanded ECM profile; also called bile duct hamartoma; are inconsequential.
  • Progressive presinusoidal fibrosis with aging can lead to gradual onset of portal hypertension, formation of APSS, ascites, and hepatic encephalopathy (HE).

Pathophysiology

  • DPMs are not associated with increased liver enzymes or jaundice until compromised by infection, choleliths, EHBDO, or choledochitis.
  • As described, different phenotypes may involve different acquired disease manifestations.
  • Choledochal cysts-not recognized until cystic luminal contents are contaminated by bacteria; ensuing infection, cyst expansion, choledochitis or EHBDO cause clinical signs; until compromised CBD, patient remains anicteric and asymptomatic.
  • Caroli's malformation-serendipitously recognized on abdominal radiography (limy gallbladder, mineralized sacculated large bile ducts), or abdominal US, when obstructed by choleliths or infected (choledochitis).
  • Diffuse DPM without extensive bridging fibrosis or presinusoidal portal hypertension-not typically associated with increased liver enzymes or jaundice and have normal total serum bile acids (TSBA); diagnosed when infection causing increase in liver enzymes leads to liver biopsy.
  • Diffuse DPM with bridging fibrosis (CHF) causes presinusoidal portal hypertension-may present for ascites, increased TSBA, ± increased liver enzymes reflecting secondary cholangitis.

Systems Affected

  • Liver-microhepatia, normal, or large liver; gallbladder agenesis, maldevelopment of left liver lobes; rare concurrent congenital intrahepatic or extrahepatic congenical portosystemic vascular anomaly (shunt, PSVA); jaundice due to EHBDO from choledochal cyst, or cholelithiasis (Caroli's malformation, choledochal cyst), or increased liver enzymes from suppurative cholangitis.
  • Gastrointestinal-anorexia; intermittent vomiting or diarrhea reflecting concurrent IBD or enteric hypertensive vasculopathy (splanchnic hypertension from presinusoidal ECM deposition).
  • Nervous-episodic HE.
  • Musculoskeletal-stunted growth and poor body condition: chronic disease, inappetence, enteric malassimilation. Urogenital-polyuria and polydipsia; possible polycystic renal phenotype; ammonium biurate urolithiasis reflects APSS or rare PSVA.
  • Hemic/Lymphatic/Immune-RBC microcytosis due to APSS; neutrophilic leukocytosis with toxic neutrophils and left-shifted leukon in suppurative cholangitis/choledochitis, choledochal cyst.

Signalment

  • Dog and cat, no sex predilection.
  • Juvenile and young adults; dogs: mean age 1.5–2.5 years (0.2–12) years.
  • May affect multiple littermates.
  • Boxer dogs may be predisposed.
  • Persian cats with polycystic renal disease predisposed.

Signs

  • May be asymptomatic.
  • Stunted growth, poor body condition if APSS.
  • GI signs: inappetence, emesis, diarrhea, enteric hemorrhage; especially if concurrent IBD.
  • PU/PD if APSS or polycystic renal disease.
  • ± Increased liver enzymes.
  • ± Fever, leukocytosis, increased bilirubin: septic choledochitis, choledochal cyst, or cholelithiasis.
  • ± Abdominal distention: ascites with APSS.
  • ± Episodic CNS signs due to HE.
  • ± Urolithiasis (ammonium urates) reflect hyperammonemia due to APSS or rare PSVA.

Causes & Risk Factors

  • Congenital malformation; suspected gene mutations affecting structure or function of primary cilia have not been proven in dogs.
  • Clinical signs usually caused by acquired complications, see previously.

Diagnosis ⬆ ⬇

Diagnosis

Differential Diagnosis

  • Stunted growth, increased total serum bile acids-PSVA, portal atresia, splanchnic portal venous thromboembolism (TE).
  • Increased liver enzymes with or without hyperbilirubinemia-chronic hepatitis, toxicity, cholangiohepatitis, choledochitis, cholecystitis.
  • Jaundice-acute liver injury, toxic injury, chronic hepatitis, copper associated hepatopathy, cholelithiasis, ruptured gallbladder (if GB cannnot be imaged), EHBDO, hemolysis-check RBC morphology for schistocytes, acanthocytes, spherocytes, Coombs' test.
  • CNS signs-infectious disorders (distemper); toxicities (lead); hydrocephalus; epilepsy; metabolic disorders (hypoglycemia, hypokalemia, hyperkalemia, hypophosphatemia); Wernicke/s encephalopathy (thiamine deficiency).
  • Ascites-Pure Transudate, many causes (see Portal Hypertension).
  • HE-APSS or PSVA or Portal TE.

CBC/Biochemistry/Urinalysis

  • CBC-RBC microcytosis: reflects APSS; target cells in dogs.
  • Biochemistry-if APSS: ± low albumin, cholesterol, BUN, variable globulin; all DPM phenotypes: ± increased ALP and ALT activity; hyperbilirubinemia: if EHBDO due to choledochal cyst or cholelithiasis or if septic.
  • Urinalysis-ammonium biurate crystalluria if APSS in CHF phenotype.

Other Laboratory Tests

Routine Coagulation Tests

Variable abnormalities (see Coagulopathy of Liver Disease). Low protein C and antithrombin activity may reflect APSS in CHF phenotype.

TSBA

Increased with shunting pattern if APSS or rare PSVA.

Peritoneal Fluid Analysis

Pure transudate (protein <2.5 g/dL); modified transudate if chronic-only in CHF phenotype.

Imaging

Radiography

  • Abdominal radiography: variable liver size (microhepatia to large liver, e.g., severe polycystic liver disease in cats.
  • Abdominal effusion: APSS in CHF phenotype.
  • Ammonium biurate calculi-radiolucent unless radiodense mineral shell; implies APSS.
  • Thoracic radiography-normal: rule out right-sided heart disease or pericardial tamponade.

Abdominal Ultrasonography

  • Variable liver size: small to large.
  • GB may not be discovered: atresia possible.
  • May disclose parenchymal or biliary system changes due to malformations (sacculated or cystic ductal structures); variable liver texture; unremarkable vasculature to portal hypoperfusion.
  • Choledochal cyst-may be difficult to image owing to overlying enteric gas and confusion with CBD and cystic duct.
  • Abdominal effusion: if APSS in CHF.
  • APSS-confirm using color-flow Doppler; may confirm hepatofugal portal flow (away from the liver); tortuous APSS usually adjacent or caudal to left kidney, adjacent to splenic vasculature; rule out portal TE and hepatic AV malformations.
  • Uroliths: renal pelvis, urinary bladder; obstructive uropathy: urethral obstruction.

Additional Imaging

Colorectal (CRS) or Splenoportal (SPS) Scintigraphy

  • Technetium-99m pertechnetate; gamma camera imaging documents isotope appearance in heart before liver to confirm shunting; shunt fraction (time activity plot) is not quantitatively reliable; normal shunt fraction 15% CRS. Sensitive noninvasive test-confirms shunting; cannot differentiate PSVA from APSS or intrahepatic from extrahepatic PSVA.
  • SPS: requires splenic injection with contrast; same principle, can miss caudal PSVA.

Multisector CT

  • Gold standard imaging to confirm APSS or PSVA; demonstrates arterial and portal circulations, may disclose asymmetric liver development, GB atresia, choledochal cyst, sacculated interlobular and cystic ducts.
  • Non-invasive test: IV contrast administration and short-term (20 minutes) general anesthesia.

Diagnostic Procedures

  • Fine-needle aspiration cytology-cannot diagnose DPM, can sometimes identify bacteria.
  • Liver biopsy-open surgical wedge or laparoscopic cup samples from several liver lobes are best, record symmetry of liver lobes sampled, needle core samples can often diagnose DPM.

Echocardiography

Rule out right-sided heart disease and vena caval occlusion (see Portal Hypertension).

Diagnostic Procedures

  • Liver biopsy: as described above.
  • Portal hypertension: >13 cmH2O attenuated by APSS; measurement may be hazardous and is not clinically useful.

Pathologic Findings

  • Gross-depends on phenotype. (1) Choledochal cyst variable size (as large as 10 cm; wall thick or thin; contents acholic and mucinous white bile; purulent, or bile laden; may be abscessed; may envelop CBD. (2) Caroli's malformation: grossly distended hepatic, interlobular, and segmental bile ducts, thick walls if choledochitis, may be mineralized, may have pigment-calcium carbonate choleliths. (3) Diffuse DPM: firm fibrotic parenchyma, fine nodular to smooth surface, may have splanchnic APSS if CHF phenotype. (4) von Meyenburg complexes: inapparent or tiny pale foci. In phenotypes 2 and 3 above, possible GB atresia, PSVA, other vascular malformation, or left-sided liver agenesis.
  • Microscopic-variable severity as previously described. Portal hypoperfusion with diffuse DPM and CHF phenotype; direct intersection of proliferative bile ductules and hepatocytes is a unique feature; islands of hepatocytes encircled by portal-to-portal bridging partitions of variable width in the CHF phenotype.

Treatment ⬆ ⬇

Treatment

Appropriate Health Care

  • Inpatient-for septic complications of choledochal cyst or DPM cholangitis or severe HE (see Hepatic Encephalopathy; Hepatitis, Suppurative and Hepatic Abscess; Cholangitis/Cholangiohepatitis Syndrome).
  • Surgical intervention: choledochal cyst-best managed by resection; depends on anatomic malformation and location; may be marsupialized or anastomosed to intestine. Attempt to use alcohol ablation not advised.
  • Outpatient-stable patients.
  • Avoid endoparasitism.
  • Treat infections promptly-DPM patients (except VMC) predisposed to cholangitis, choledochitis due to blind ended non-contiguous ductal structures; in CHF portal venous hypoperfusion reduces Kupffer cell surveillance.
  • In CHF: remain vigilant for ammonium biurate obstructive uropathies (all levels of urinary system); urethral obstruction (males) may require permanent urethrostomy.
  • If APSS-avoid NSAIDs which may augment ascites (sodium and water retention) and gastrointestinal bleeding provoking HE.

Nursing Care

Hepatic Encephalopathy

  • Eliminate causal factors of HE; individualize diet, supplement water-soluble vitamins, vitamin E, and K depending on PT or PIVKA test; optimize HE management to individual response (see Hepatic Encephalopathy). Strive to maintain body condition and muscle mass-muscle mass attenuates ammonia toxicity as temporary storage site; provide multiple small feedings daily.
  • Ascites (see Portal Hypertension).

Medications ⬆ ⬇

Medications

Drug(s) Of Choice

Hepatic Encephalopathy

  • Lactulose (0.5–1.0 mL/kg PO q8–12h)-goal to maintain several soft stools daily; may withdraw with optimal diet modifications.
  • Oral antibiotics to modify encephalogenic enteric toxin production-first choices: metronidazole (7.5 mg/kg PO q12h) or amoxicillin (22 mg/kg PO q12h). Avoid neomycin (20 mg/kg PO q8–12h PO)-has potential for enteric absorption (esp. if concurrent IBD) causing ototoxicity (deafness) and nephrotoxicity [chronic neomycin: ∼ 3% absorbed per dose].

Ascites (also see Portal Hypertension)

  • Dietary sodium restriction (see Portal Hypertension; Portosystemic Shunting, Acquired)
  • Diuretics: Furosemide (1–4 mg/kg PO, IM, or IV q12–24h)-potassium wasting effect modulated by combination with spironolactone (1–4 mg/kg PO q12h, loading dose then maintenance dose of 2–4 mg/kg; potassium sparing; less potent than furosemide (see Portal Hypertension; Portosystemic Shunting, Acquired).
  • Diuretic-resistant ascites-consider therapeutic abdominocentesis, V2 receptor antagonists, and angiotensin receptor blocker diuretic (see Portal Hypertension for details).
  • Antifibrotic-in humans with DPM, traditional antifibrotics have no influence on age-related accrual of portal ECM causing presinusoidal portal hypertension. The only drug with some efficacy in rat model of adult polycystic renal disease (with CHF) is telmisartan.
  • Telmisartan is an angiotensin receptor blocker (ARB) used widely in humans as an antihypertensive with partial PPAR-γ agonist activity; it also is nephroprotective (diabetes, other forms of renal injury), prevents certain forms of drug-induced hepatotoxicity, and reduces hepatic fibrosis. ARBs-selectively antagonize the angiotensin-1 receptor, bypassing intermediary activation steps within the RAAS cascade. Telmisartan administration PO to healthy dogs at 1.0 mg/kg/day significantly increased urine volume and sodium excretion and was safely used (single case report) for amelioration of pathologic proteinuria in a dog; effective, non-toxic at escalating doses of 0.43 mg/kg PO q24h to 0.9 mg/kg/day.

Antioxidant Medications

Indicated in dogs with chronic cholangitis, increased liver enzymes, or CHF (see Cirrhosis and Fibrosis of the Liver).

Bleeding Tendencies

See Coagulopathy of Liver Disease. Rare in CHF; may encounter in chronic EHBDO caused by choledochal cyst or cholelithiasis.

Gastrointestinal Hemorrhage

See Cirrhosis and Fibrosis of the Liver; Portal Hypertension. Hypertensive enteric vasculopathy may be encountered with CHF because of APSS.

Contraindications/Possible Interactions

  • Avoid or reduce dosage of drugs relying on hepatic biotransformation or first pass hepatic metabolism; avoid drugs reacting with GABA-benzodiazepine receptors; avoid drugs inhibiting biotransformation and metabolism of other drugs (e.g., cimetidine, chloramphenicol, quinidine, some calcium channel blockers).
  • Avoid metoclopramide if spironolactone used as a diuretic (augments aldosterone).

Follow-Up ⬆ ⬇

Follow-Up

Patient Monitoring

  • Biochemistry-initially, monitor q2–4 weeks until stabile in animals presenting with sepsis or EHBDO, then q4–6 months or if cyclically ill or febrile; monitor for recurrent septic cholangitis/choledochitis, development of septic effusion; HE decompensation. If colchicine used for fibrosis (NOTE: not recommended), monitor CBC for bone marrow suppression and observe for enteric toxicity and neurotoxicity.

Possible Complications

CHF associated with HE-requires indefinite nutritional and medical management.

Expected Course and Prognosis

  • Long-term survival (years) possible.
  • Short-term or life-long treatments may be required-antibiotics, unknown long-term benefit from antifibrotics, necessary nutritional modifications if APSS in CHF, ancillary treatments for HE and hypertensive portal vasculopathy (enteric hemorrhage, inappetence), and ascites.
  • 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.

Miscellaneous ⬆

Miscellaneous

Associated Conditions

  • Hepatic encephalopathy
  • Ascites
  • Gastrointestinal bleeding
  • APSS

Age-Related Factors

  • Prognosis depends on: (1) degree of fibrosis and APSS in CHF, (2) severity of relapsing septic cholangitis or choledochal cyst infection, (3) intrahepatic infectious cholelithiasis, and (4) evidence of hepatic insufficiency at initial diagnosis.
  • Fibrosis likely progressive with aging.

Zoonotic Potential

N/A

Abbreviations

  • ACT = activated clotting time
  • ALP = alkaline phosphatase
  • ALT = alanine aminotransferase
  • APSS = acquired portosystemic shunts
  • APTT = activated partial thromboplastin time
  • AV = arteriovenous
  • BUN = blood urea nitrogen
  • CBD = common bile duct
  • CHF = congenital hepatic fibrosis
  • CNS = central nervous system
  • DPM = ductal plate malformation
  • GI = gastrointestinal
  • HE = hepatic encephalopathy
  • IBD = inflammatory bowel disease
  • MVD = hepatoportal microvascular dysplasia
  • NSAID = nonsteroidal anti-inflammatory drug
  • PIVKA = proteins invoked by vitamin K absence or antagonism
  • PSVA = portosystemic vascular anomaly
  • PT = prothrombin time
  • TE = thromboembolism
  • TSBA = total serum bile acids
  • VMC = von Meyenberg complex

Author Sharon A. Center

Consulting Editor Sharon A. Center

Suggested Reading

Brown DL, Van Winkle T, Cecere T, et al. Congenital hepatic fibrosis in 5 dogs. Vet Pathol 2010, 47:102–107.

Bugbee AC1, Coleman AE, Wang A, et al. Telmisartan treatment of refractory proteinuria in a dog. J Vet Intern Med 2014, 28:1871–1874.

Rutgers , HC, Haywood , S, Kelly , DF. Idiopathic hepatic fibrosis in 15 dogs. Vet Rec 1993, 133:115–118.