J Korean Med Sci.  2023 Sep;38(38):e296. 10.3346/jkms.2023.38.e296.

Factors Associated With the Development and Severity of Polycystic Liver in Patients With Autosomal Dominant Polycystic Kidney Disease

• Kim Y
• Park HC
• Ryu H
• Kim YC
• Ahn C
• Lee KB
• Kim YH
• Han S
• Bae EH
• Jeong K
• Choi J
• Oh KH
• Oh YK

• KMID: 2546219
• DOI: http://doi.org/10.3346/jkms.2023.38.e296

Abstract

Background
Factors related to the development and severity of polycystic liver disease (PLD) have not been well established. We aimed to evaluate the genetic and epidemiologic risk factors of PLD in patients with autosomal dominant polycystic kidney disease (ADPKD).
Methods
Adult patients with inherited cystic kidney disease were enrolled from May 2019 to May 2021. Demographic, clinical, and laboratory data were collected at the initial study visit. The severity of PLD was graded based on the height-adjusted total liver volume: < 1,000 mL/m (Gr1), 1,000–1,800 mL/m (Gr2), and > 1,800 mL/m (Gr3). Targeted exome sequencing was done by a gene panel including 89 ciliopathy-related genes. We searched out the relative factors to the presence and the severity of PLD using logistic regression analysis.
Results
Of 602 patients with typical ADPKD, 461 (76.6%) patients had PLD. The patients with PLD showed female predominance and a higher frequency of other ADPKD-related complications. The genetic variants with truncating mutation of PKD1 (PKD1-proteintruncating [PT]) or PKD2 commonly affected the development and severity of PLD. An older age, female sex, and higher kidney volume with Mayo classification 1C-1E was significantly associated with the development of PLD, but not with the severity of PLD. On the other hand, higher body mass index, lower hemoglobin, and higher alkaline phosphatase (ALP) were the significant risk factors of severe PLD (≥ Gr2).
Conclusion
Hepatic involvement in ADPKD could be related to kidney manifestations and genetic variants including PKD1-PT or PKD2. Monitoring hemoglobin and ALP and evaluating the genetic variants might help predict severe PLD.

Keyword

Polycystic Kidney; Autosomal Dominant; Polycystic Liver Disease; Risk Factors; Genotype

Figure

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  Fig. 1 Study populations.CT = computed tomography, PKD = polycystic kidney disease.

Reference

1. Bae KT, Zhu F, Chapman AB, Torres VE, Grantham JJ, Guay-Woodford LM, et al. Magnetic resonance imaging evaluation of hepatic cysts in early autosomal-dominant polycystic kidney disease: the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease cohort. Clin J Am Soc Nephrol. 2006; 1(1):64–69. PMID: 17699192.

2. Hogan MC, Abebe K, Torres VE, Chapman AB, Bae KT, Tao C, et al. Liver involvement in early autosomal-dominant polycystic kidney disease. Clin Gastroenterol Hepatol. 2015; 13(1):155–64.e6. PMID: 25111236.

3. Abu-Wasel B, Walsh C, Keough V, Molinari M. Pathophysiology, epidemiology, classification and treatment options for polycystic liver diseases. World J Gastroenterol. 2013; 19(35):5775–5786. PMID: 24124322.

4. Gabow PA, Johnson AM, Kaehny WD, Manco-Johnson ML, Duley IT, Everson GT. Risk factors for the development of hepatic cysts in autosomal dominant polycystic kidney disease. Hepatology. 1990; 11(6):1033–1037. PMID: 2365280.

5. Sherstha R, McKinley C, Russ P, Scherzinger A, Bronner T, Showalter R, et al. Postmenopausal estrogen therapy selectively stimulates hepatic enlargement in women with autosomal dominant polycystic kidney disease. Hepatology. 1997; 26(5):1282–1286. PMID: 9362373.

6. D’Agnolo HM, Casteleijn NF, Gevers TJ, de Fijter H, van Gastel MD, Messchendorp AL, et al. The association of combined total kidney and liver volume with pain and gastrointestinal symptoms in patients with later stage autosomal dominant polycystic kidney disease. Am J Nephrol. 2017; 46(3):239–248. PMID: 28881341.

7. Neijenhuis MK, Kievit W, Perrone RD, Sloan JA, Erwin P, Murad MH, et al. The effect of disease severity markers on quality of life in autosomal dominant polycystic kidney disease: a systematic review, meta-analysis and meta-regression. BMC Nephrol. 2017; 18(1):169. PMID: 28545401.

8. Ryu H, Kim H, Park HC, Kim H, Cho EJ, Lee KB, et al. Total kidney and liver volume is a major risk factor for malnutrition in ambulatory patients with autosomal dominant polycystic kidney disease. BMC Nephrol. 2017; 18(1):22. PMID: 28088190.

9. Chandok N. Polycystic liver disease: a clinical review. Ann Hepatol. 2012; 11(6):819–826. PMID: 23109444.

10. Kim H, Sung J, Bae JY, Lee P, Oh YK, Kim H. Identification of osteopontin as a urinary biomarker for autosomal dominant polycystic kidney disease progression. Kidney Res Clin Pract. 2022; 41(6):730–740. PMID: 35791741.

11. Radhakrishnan Y, Duriseti P, Chebib FT. Management of autosomal dominant polycystic kidney disease in the era of disease-modifying treatment options. Kidney Res Clin Pract. 2022; 41(4):422–431. PMID: 35354242.

12. Chebib FT, Jung Y, Heyer CM, Irazabal MV, Hogan MC, Harris PC, et al. Effect of genotype on the severity and volume progression of polycystic liver disease in autosomal dominant polycystic kidney disease. Nephrol Dial Transplant. 2016; 31(6):952–960. PMID: 26932689.

13. Kataoka H, Watanabe S, Sato M, Manabe S, Makabe S, Akihisa T, et al. Predicting liver cyst severity by mutations in patients with autosomal-dominant polycystic kidney disease. Hepatol Int. 2021; 15(3):791–803. PMID: 33811288.

14. Pei Y, Obaji J, Dupuis A, Paterson AD, Magistroni R, Dicks E, et al. Unified criteria for ultrasonographic diagnosis of ADPKD. J Am Soc Nephrol. 2009; 20(1):205–212. PMID: 18945943.

15. Park HC, Ryu H, Kim YC, Ahn C, Lee KB, Kim YH, et al. Genetic identification of inherited cystic kidney diseases for implementing precision medicine: a study protocol for a 3-year prospective multicenter cohort study. BMC Nephrol. 2021; 22(1):2. PMID: 33407230.

16. Irazabal MV, Rangel LJ, Bergstralh EJ, Osborn SL, Harmon AJ, Sundsbak JL, et al. Imaging classification of autosomal dominant polycystic kidney disease: a simple model for selecting patients for clinical trials. J Am Soc Nephrol. 2015; 26(1):160–172. PMID: 24904092.

17. Bevilacqua MU, Hague CJ, Romann A, Sheitt H, Vasilescu DM, Yi TW, et al. CT of kidney volume in autosomal dominant polycystic kidney disease: accuracy, reproducibility, and radiation dose. Radiology. 2019; 291(3):660–667. PMID: 30964424.

18. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009; 150(9):604–612. PMID: 19414839.

19. Lemaigre FP. Molecular mechanisms of biliary development. Prog Mol Biol Transl Sci. 2010; 97:103–126. PMID: 21074731.

20. de Miranda Henriques MS, de Morais Villar EJ. Chapter 17. The liver and polycystic kidney disease. Li X, editor. Polycystic Kidney Disease. Brisbane, Australia: Codon Publications;2015. p. 425–441.

21. Hoevenaren IA, Wester R, Schrier RW, McFann K, Doctor RB, Drenth JP, et al. Polycystic liver: clinical characteristics of patients with isolated polycystic liver disease compared with patients with polycystic liver and autosomal dominant polycystic kidney disease. Liver Int. 2008; 28(2):264–270. PMID: 17927714.

22. Alvaro D, Mancino MG, Onori P, Franchitto A, Alpini G, Francis H, et al. Estrogens and the pathophysiology of the biliary tree. World J Gastroenterol. 2006; 12(22):3537–3545. PMID: 16773710.

23. Gevers TJ, Inthout J, Caroli A, Ruggenenti P, Hogan MC, Torres VE, et al. Young women with polycystic liver disease respond best to somatostatin analogues: a pooled analysis of individual patient data. Gastroenterology. 2013; 145(2):357–365.e1. PMID: 23665274.

24. Gabow PA, Johnson AM, Kaehny WD, Kimberling WJ, Lezotte DC, Duley IT, et al. Factors affecting the progression of renal disease in autosomal-dominant polycystic kidney disease. Kidney Int. 1992; 41(5):1311–1319. PMID: 1614046.

25. Adin ME. Liver involvement in autosomal dominant polycystic kidney disease. N Engl J Med. 2019; 380(20):1954. PMID: 31091376.

26. Chapman AB, Guay-Woodford LM, Grantham JJ, Torres VE, Bae KT, Baumgarten DA, et al. Renal structure in early autosomal-dominant polycystic kidney disease (ADPKD): the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) cohort. Kidney Int. 2003; 64(3):1035–1045. PMID: 12911554.

27. Torres VE, King BF, Chapman AB, Brummer ME, Bae KT, Glockner JF, et al. Magnetic resonance measurements of renal blood flow and disease progression in autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol. 2007; 2(1):112–120. PMID: 17699395.

28. Lubel JS, Angus PW. Modern management of portal hypertension. Intern Med J. 2005; 35(1):45–49. PMID: 15667468.

29. Lubel JS, Herath CB, Burrell LM, Angus PW. Liver disease and the renin-angiotensin system: recent discoveries and clinical implications. J Gastroenterol Hepatol. 2008; 23(9):1327–1338. PMID: 18557800.

30. Gonzalez-Casas R, Jones EA, Moreno-Otero R. Spectrum of anemia associated with chronic liver disease. World J Gastroenterol. 2009; 15(37):4653–4658. PMID: 19787828.

31. Siddique A, Nelson JE, Aouizerat B, Yeh MM, Kowdley KV. NASH Clinical Research Network. Iron deficiency in patients with nonalcoholic fatty liver disease is associated with obesity, female gender, and low serum hepcidin. Clin Gastroenterol Hepatol. 2014; 12(7):1170–1178. PMID: 24269922.

32. Cnossen WR, Drenth JP. Polycystic liver disease: an overview of pathogenesis, clinical manifestations and management. Orphanet J Rare Dis. 2014; 9(1):69. PMID: 24886261.

33. Simbrunner B, Beer A, Wöran K, Schmitz F, Primas C, Wewalka M, et al. Portal hypertensive gastropathy is associated with iron deficiency anemia. Wien Klin Wochenschr. 2020; 132(1-2):1–11.

34. Van Keimpema L, De Koning DB, Van Hoek B, Van Den Berg AP, Van Oijen MG, De Man RA, et al. Patients with isolated polycystic liver disease referred to liver centres: clinical characterization of 137 cases. Liver Int. 2011; 31(1):92–98. PMID: 20408955.

35. Alvaro D, Benedetti A, Marucci L, Delle Monache M, Monterubbianesi R, Di Cosimo E, et al. The function of alkaline phosphatase in the liver: regulation of intrahepatic biliary epithelium secretory activities in the rat. Hepatology. 2000; 32(2):174–184. PMID: 10915721.

36. Poupon R. Liver alkaline phosphatase: a missing link between choleresis and biliary inflammation. Hepatology. 2015; 61(6):2080–2090. PMID: 25603770.

37. Rossetti S, Consugar MB, Chapman AB, Torres VE, Guay-Woodford LM, Grantham JJ, et al. Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2007; 18(7):2143–2160. PMID: 17582161.

38. Kataoka H, Fukuoka H, Makabe S, Yoshida R, Teraoka A, Ushio Y, et al. Prediction of renal prognosis in patients with autosomal dominant polycystic kidney disease using PKD1/PKD2 mutations. J Clin Med. 2020; 9(1):146. PMID: 31948117.

39. Carrera P, Calzavara S, Magistroni R, den Dunnen JT, Rigo F, Stenirri S, et al. Deciphering variability of PKD1 and PKD2 in an Italian cohort of 643 patients with autosomal dominant polycystic kidney disease (ADPKD). Sci Rep. 2016; 6(1):30850. PMID: 27499327.

40. Hwang YH, Conklin J, Chan W, Roslin NM, Liu J, He N, et al. Refining genotype-phenotype correlation in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2016; 27(6):1861–1868. PMID: 26453610.

41. Kim H, Park HC, Ryu H, Kim H, Lee HS, Heo J, et al. Genetic characteristics of Korean patients with autosomal dominant polycystic kidney disease by targeted exome sequencing. Sci Rep. 2019; 9(1):16952. PMID: 31740684.

42. Lanktree MB, Iliuta IA, Haghighi A, Song X, Pei Y. Evolving role of genetic testing for the clinical management of autosomal dominant polycystic kidney disease. Nephrol Dial Transplant. 2019; 34(9):1453–1460. PMID: 30165646.

43. Cornec-Le Gall E, Torres VE, Harris PC. Genetic complexity of autosomal dominant polycystic kidney and liver diseases. J Am Soc Nephrol. 2018; 29(1):13–23. PMID: 29038287.