Liver involvement in early autosomal-dominant polycystic kidney disease

Abstract

Background & aims: Polycystic liver disease (PLD), the most common extrarenal manifestation of autosomal-dominant polycystic kidney disease (ADPKD), has become more prevalent as a result of increased life expectancy, improved renal survival, reduced cardiovascular mortality, and renal replacement therapy. No studies have fully characterized PLD in large cohorts. We investigated whether liver and cyst volumes are associated with volume of the hepatic parenchyma, results from liver laboratory tests, and patient-reported outcomes.

Methods: We performed a cross-sectional analysis of baseline liver volumes, measured by magnetic resonance imaging, and their association with demographics, results from liver laboratory and other tests, and quality of life. The data were collected from a randomized, placebo-controlled trial underway at 7 tertiary-care medical centers to determine whether the combination of an angiotensin I-converting enzyme inhibitor and angiotensin II-receptor blocker was superior to the inhibitor alone, and whether low blood pressure (<110/75 mm Hg) was superior to standard blood pressure (120-130/70-80 mm Hg), in delaying renal cystic progression in 558 patients with ADPKD, stages 1 and 2 chronic kidney disease, and hypertension (age, 15-49 y).

Results: We found hepatomegaly to be common among patients with ADPKD. Cysts and parenchyma contributed to hepatomegaly. Cysts were more common and liver and cyst volumes were greater in women, increasing with age. Patients with advanced disease had a relative loss of liver parenchyma. We observed small abnormalities in results from liver laboratory tests, and that splenomegaly and hypersplenism were associated with PLD severity. Higher liver volumes were associated with a lower quality of life.

Conclusions: Hepatomegaly is common even in early stage ADPKD and is not accounted for by cysts alone. Parenchymal volumes were larger, compared with liver volumes of patients without ADPKD or with those predicted by standardized equations, even among patients without cysts. The severity of PLD was associated with altered biochemical and hematologic features, as well as quality of life. ClinicalTrials.gov identifier: NCT00283686.

Keywords: CKD; HALT-PKD-A; Hepatic Cyst; MRI Analysis.

Figure 1. Effects of sex on height adjusted total liver volume (HtLV) and relationship of HtLV to height adjusted liver parenchymal volume (HtLPV)

(A) Distribution of liver cyst volumes (HtLCV) in relation to HtLVs. A subpopulation of women have more severe PLD with higher HtLCV. (B) Plot of HtLPV and HtLCV versus HtLV. As HtLV increases, HtLPV also increases, but then plateaus. Interrupted diagonal line (slope=1) denotes the maximum values for HtLPV and HtLCV indicating HtLPV closely parallels HtLV for the majority of individuals until HtLV reaches ~1800 mL/m (vertical interrupted line). To illustrate this, the patient with liver cysts and mildest disease (lower left) had HtLV 475 mL/m (mild disease; HtLV<1000ml/m, vertical interrupted line), HtLCV 1 mL/m, and HtLPV 475 mL/m, and the most severe case (points farthest right) had HtLV of 6382 mL/m, HtLCV of 5287 mL/m, and HtLPV of 1095mL/m but their HtLPV is no different than less severe PLD cases with lower HtLVs. X and Y axes are log scale in both figures. The correlation between log (HtLV) and log (HtLPV) was r=0.65 (P<0.001). Note second vertical interrupted line (HtLV>1800 mL/m), the cutoff point for HtLV that delineated Group 3 or the group with the highest htLVs (see Table 3). To the right of the graph are two additional vertical lines delineating HtLVs ≥2x those of normal female (1x=1858 mL/m) and male (1x= 1986 mL/m) controls.

Figure 1. Effects of sex on height adjusted total liver volume (HtLV) and relationship of HtLV to height adjusted liver parenchymal volume (HtLPV)

(A) Distribution of liver cyst volumes (HtLCV) in relation to HtLVs. A subpopulation of women have more severe PLD with higher HtLCV. (B) Plot of HtLPV and HtLCV versus HtLV. As HtLV increases, HtLPV also increases, but then plateaus. Interrupted diagonal line (slope=1) denotes the maximum values for HtLPV and HtLCV indicating HtLPV closely parallels HtLV for the majority of individuals until HtLV reaches ~1800 mL/m (vertical interrupted line). To illustrate this, the patient with liver cysts and mildest disease (lower left) had HtLV 475 mL/m (mild disease; HtLV<1000ml/m, vertical interrupted line), HtLCV 1 mL/m, and HtLPV 475 mL/m, and the most severe case (points farthest right) had HtLV of 6382 mL/m, HtLCV of 5287 mL/m, and HtLPV of 1095mL/m but their HtLPV is no different than less severe PLD cases with lower HtLVs. X and Y axes are log scale in both figures. The correlation between log (HtLV) and log (HtLPV) was r=0.65 (P<0.001). Note second vertical interrupted line (HtLV>1800 mL/m), the cutoff point for HtLV that delineated Group 3 or the group with the highest htLVs (see Table 3). To the right of the graph are two additional vertical lines delineating HtLVs ≥2x those of normal female (1x=1858 mL/m) and male (1x= 1986 mL/m) controls.

Figure 2. MR images illustrating

(A) Hepatomegaly (TLV 2677 mL) with larger contribution of LPV (2576 mL) compared to LCV (101 mL); (B) Hepatomegaly (11834 mL) with larger contribution of LCV (9806 mL) compared to LPV (2028 mL); (C) Splenomegaly (601 mL) associated with severe PLD(3388 mL) with LCV (1044 mL); (D) Splenomegaly (542 mL) associated with moderate PLD (LV 2082 mL, LCV 110 mL) (E) Pancreatic cyst (diameter 21.8 mm) (F) Splenic cysts (diameter 12.2 mm).