Estrogen-Containing Oral Contraceptives Are Associated With Polycystic Liver Disease Severity in Premenopausal Patients.

The association between estrogen-containing oral contraceptives and history of pregnancies with disease severity in women with polycystic liver disease (PLD) is unclear. We performed a cross-sectional cohort study to assess this association by selecting female patients with PLD of which imaging was available prior to any liver volume-reducing therapy. Patients received a questionnaire to collect detailed information on estrogen use and pregnancies. Preplanned subgroup analyses were performed on premenopausal and postmenopausal patients. The questionnaire was returned by 287 of 360 selected patients (80%). There was no significant association between estrogen-containing oral contraceptives and height-adjusted total liver volume (hTLV) in the total group (P = 0.06) and postmenopausal subgroup (P = 0.7). By contrast, each year of exposure corresponds with a 1.45% higher hTLV (P = 0.02) in the premenopausal subgroup, equivalent to a 15.5% higher hTLV for every 10 years of use. Pregnancy duration was not associated with hTLV. In conclusion, patients with PLD should avoid exogenous estrogens.

Lanreotide Reduces Liver Growth In Patients With Autosomal Dominant Polycystic Liver and Kidney Disease.

BACKGROUND & AIMS: Polycystic liver disease is the most common extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD). There is need for robust long-term evidence for the volume-reducing effect of somatostatin analogues. We made use of data from an open-label, randomized trial to determine the effects of lanreotide on height-adjusted liver volume (hTLV) and combined height-adjusted liver and kidney volume (hTLKV) in patients with ADPKD. METHODS: We performed a 120-week study comparing the reno-protective effects of lanreotide vs standard care in 305 patients with ADPKD (the DIPAK-1 study). For this analysis, we studied the 175 patients with polycystic liver disease with hepatic cysts identified by magnetic resonance imaging and liver volume ≥2000 mL. Of these, 93 patients were assigned to a group that received lanreotide (120 mg subcutaneously every 4 weeks) and 82 to a group that received standard care (blood pressure control, a sodium-restricted diet, and antihypertensive agents). The primary endpoint was percent change in hTLV between baseline and end of treatment (week 120). A secondary endpoint was change in hTLKV. RESULTS: At 120 weeks, hTLV decreased by 1.99% in the lanreotide group (95% confidence interval [CI], -4.21 to 0.24) and increased by 3.92% in the control group (95% CI, 1.56-6.28). Compared with the control group, lanreotide reduced the growth of hTLV by 5.91% (95% CI, -9.18 to -2.63; P < .001). Growth of hTLV was still reduced by 3.87% at 4 months after the last injection of lanreotide compared with baseline (95% CI, -7.55 to -0.18; P = .04). Lanreotide reduced growth of hTLKV by 7.18% compared with the control group (95% CI, -10.25 to -4.12; P < .001). CONCLUSIONS: In this subanalysis of a randomized trial of patients with polycystic liver disease due to ADPKD, lanreotide for 120 weeks reduced the growth of liver and combined liver and kidney volume. This effect was still present 4 months after the last injection of lanreotide. ClinicalTrials.gov, Number: NCT01616927.

Severity in polycystic liver disease is associated with aetiology and female gender: Results of the International PLD Registry.

BACKGROUND & AIMS: Polycystic liver disease (PLD) occurs in two genetic disorders, autosomal-dominant polycystic kidney disease (ADPKD) and autosomal-dominant polycystic liver disease (ADPLD). The aim of this study is to compare disease severity between ADPKD and ADPLD by determining the association between diagnosis and height-adjusted total liver volume (hTLV). METHODS: We performed a cross-sectional analysis with hTLV as endpoint. Patients were identified from the International PLD Registry (>10 liver cysts) and included in our analysis when PLD diagnosis was made prior to September 2017, hTLV was available before volume-reducing therapy (measured on computed tomography or magnetic resonance imaging) and when patients were tertiary referred. Data from the registry were retrieved for age, diagnosis (ADPKD or ADPLD), gender, height and hTLV. RESULTS: A total of 360 patients (ADPKD n = 241; ADPLD n = 119) met our inclusion criteria. Female ADPKD patients had larger hTLV compared with ADPLD (P = 0.008). In a multivariate regression analysis, ADPKD and lower age at index CT were independently associated with larger hTLV in females, whereas in males a higher age was associated with larger hTLV. Young females (≤51 years) had larger liver volumes compared with older females (>51 years) in ADPKD. CONCLUSION: Aetiology is presented as a new risk factor associated with PLD severity. Young females with ADPKD represent a subgroup of PLD patients with the most severe phenotype expressed in hTLV.

Effect of Lanreotide on Kidney Function in Patients With Autosomal Dominant Polycystic Kidney Disease: The DIPAK 1 Randomized Clinical Trial.

Importance: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation in both kidneys and loss of renal function, eventually leading to a need for kidney replacement therapy. There are limited therapeutic management options. Objective: To examine the effect of the somatostatin analogue lanreotide on the rate of kidney function loss in patients with later-stage ADPKD. Design, Setting, and Participants: An open-label randomized clinical trial with blinded end point assessment that included 309 patients with ADPKD from July 2012 to March 2015 at 4 nephrology outpatient clinics in the Netherlands. Eligible patients were 18 to 60 years of age and had an estimated glomerular filtration rate (eGFR) of 30 to 60 mL/min/1.73 m2. Follow-up of the 2.5-year trial ended in August 2017. Interventions: Patients were randomized to receive either lanreotide (120 mg subcutaneously once every 4 weeks) in addition to standard care (n = 153) or standard care only (target blood pressure <140/90 mm Hg; n = 152). Main Outcomes and Measures: Primary outcome was annual change in eGFR assessed as slope through eGFR values during the 2.5-year treatment phase. Secondary outcomes included change in eGFR before vs after treatment, incidence of worsening kidney function (start of dialysis or 30% decrease in eGFR), change in total kidney volume and change in quality of life (range: 1 [not bothered] to 5 [extremely bothered]). Results: Among the 309 patients who were randomized (mean [SD] age, 48.4 [7.3] years; 53.4% women), 261 (85.6%) completed the trial. Annual rate of eGFR decline for the lanreotide vs the control group was -3.53 vs -3.46 mL/min/1.73 m2 per year (difference, -0.08 [95% CI, -0.71 to 0.56]; P = .81). There were no significant differences for incidence of worsening kidney function (hazard ratio, 0.87 [95% CI, 0.49 to 1.52]; P = .87), change in eGFR (-3.58 vs -3.45; difference, -0.13 mL/min/1.73 m2 per year [95% CI, -1.76 to 1.50]; P = .88), and change in quality of life (0.05 vs 0.07; difference, -0.03 units per year [95% CI, -0.13 to 0.08]; P = .67). The rate of growth in total kidney volume was lower in the lanreotide group than the control group (4.15% vs 5.56%; difference, -1.33% per year [95% CI, -2.41% to -0.24%]; P = .02). Adverse events in the lanreotide vs control group included injection site discomfort (32% vs 0.7%), injection site papule (5.9% vs 0%), loose stools (91% vs 6.6%), abdominal discomfort (79% vs 20%), and hepatic cyst infections (5.2% vs 0%). Conclusions and Relevance: Among patients with later-stage autosomal dominant polycystic kidney disease, treatment with lanreotide compared with standard care did not slow the decline in kidney function over 2.5 years of follow-up. These findings do not support the use of lanreotide for treatment of later-stage autosomal dominant polycystic kidney disease. Trial Registration: ClinicalTrials.gov Identifier: NCT01616927.

Drug holiday in patients with polycystic liver disease treated with somatostatin analogues.

BACKGROUND: Somatostatin analogues (SAs) reduce liver volume and relief symptoms in polycystic liver disease (PLD). Its effect wears off after continuing therapy suggesting development of SA tolerance in patients on chronic therapy. We postulate that a drug holiday resensitizes the liver to its acute pharmacological effects. Therefore, this study examines the liver volume-reducing effect of SAs after a drug holiday. METHODS: Patients were identified from the International PLD Registry and included in our analysis when (1) treated with SAs during two cycles separated by a drug holiday and (2) height-adjusted total liver volume (hTLV) was available at start and end of each cycle. For our primary outcome we compared the effect of SAs (in % per 6 months) on hTLV between the first and second treatment cycle. RESULTS: In 34 patients, initial liver volume-reducing effect was similar to that after rechallenge [-2.6% per 6 months (interquartile range, -3.8-0.8) versus -1.6% per 6 months (interquartile range, -3.1-1.1), p = 0.510]. Cessation of treatment led to a rebound effect, but liver volume remained stable compared with the baseline with intermittent therapy in responders to SA [-0.6% (interquartile range, -7.4-5.7) after 46.5 months]. CONCLUSIONS: PLD patients treated with SAs benefit from retreatment after a drug holiday. The significant increase of liver volume after cessation of treatment complicates widespread use of a drug holiday as new treatment strategy. Our results contribute to a better understanding of the pharmacological effect of SAs and help to identify patients who might benefit.

Clinical management of polycystic liver disease.

A 41-year old female underwent a computed tomography (CT) scan in 2010 because of symptoms suggestive of appendicitis. Incidentally, multiple liver lesions characterised as cysts were detected. The presence of small to medium sized liver cysts (diameter between <1 cm and 4 cm) in all liver segments (>100 cysts) and absence of kidney cysts in the context of normal renal function led to the clinical diagnosis of autosomal dominant polycystic liver disease (ADPLD). Five years later she was referred to the outpatient clinic with increased abdominal girth, pain in the right upper abdomen and right flank, and early satiety. She had difficulties bending over and could neither cut her toenails nor tie her shoe laces. In her early twenties she had used oral contraception for five years. She has been pregnant twice. Clinical examination showed an enlarged liver reaching into the right pelvic region and crossing the midline of the abdomen. Laboratory testing demonstrated increased gamma-glutamyl transferase (80 IU/L, normal <40 IU/L) and alkaline phosphatase (148 IU/L, normal <100 IU/L) levels. Bilirubin, albumin and coagulation times were within the normal range. A new CT scan in 2015 was compatible with an increased number and size of liver cysts. The diameter of cysts varied between <1 cm and 6 cm (anatomic distribution shown [Fig. 2B]). There were no signs of hepatic venous outflow obstruction, portal hypertension or compression on the biliary tract. Height-adjusted total liver volume (htTLV) increased from 2,667 ml/m in 2012 to 4,047 ml/m in 2015 (height 172 cm). The case we present here is not uncommon, and prompts several relevant questions.

Proton Pump Inhibitors Reduce the Frequency of Phlebotomy in Patients With Hereditary Hemochromatosis.

BACKGROUND & AIMS: Patients with hereditary hemochromatosis (HH) need frequent phlebotomies to reduce iron overload. Proton pump inhibitors (PPIs) were reported to reduce the need for phlebotomies in patients homozygous for the C282Y mutation in HFE. We investigated the effects of PPI treatment on numbers of phlebotomies in these patients. METHODS: We conducted a retrospective study of patients with HH homozygous for the C282Y mutation by using the database and medical records from Atrium Medical Centrum Parkstad in Brunssum, The Netherlands. In a paired group analysis of 12 patients, we compared mean serum levels of ferritin and number of phlebotomies needed each year during the periods of 3 years before and 3 years after the start of PPI therapy. We compared these results with those from a group who received PPIs for at least 2 years (n = 9) and a group who never received PPIs (n = 36). RESULTS: We found a significant reduction in median number of phlebotomies after patients began taking PPIs vs. before (0.50 vs. 3.17, P < .002). Patients who received PPIs for at least 2 years needed significantly fewer phlebotomies than patients in the paired group before they started taking PPIs (1.25 vs. 3.17, P < .001). The number of phlebotomies in the group who never received PPIs was significantly higher than in the paired group after they started taking PPIs (3.0 vs. 0.5, P < .001). CONCLUSIONS: On the basis of a retrospective analysis, in patients with HH homozygous for the C282Y mutation in HFE, treatment with PPIs for 2 or more years significantly reduced the number of phlebotomies required to maintain serum levels of ferritin below 100 µg/L.