Risk factors associated with pseudoaldosteronism in patients with chronic hepatitis: A retrospective cohort study

Komatsu, Akihiro; Yoshino, Tetsuhiro; Suzuki, Takeshi; Nakamura, Tomonori; Kanai, Takanori; Watanabe, Kenji

doi:10.1111/bcpt.13178

Cited by 7 publications

(6 citation statements)

References 21 publications

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“…In terms of safety, we found that OCG capsules showed a satisfactory safety profile for patients with chronic eczema, as no patients experienced serious adverse events during our study. Nevertheless, long-term use of OCG may increase the risk of some adverse events, such as pseudoaldosteronism [25,26]. Known effects of pseudoaldosteronism were observed in our study, as three (3.2%) patients developed lower extremity edema, one (1.1%) experienced hypokalemia, and two (2.1%) had new-onset high blood pressure.…”

Section: Discussionsupporting

confidence: 49%

A Multicenter, Randomized, Double‐Blind, Placebo‐Controlled Study of Compound Glycyrrhizin Capsules Combined with a Topical Corticosteroid in Adults with Chronic Eczema

Mei

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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Background. Glycyrrhizin is widely used in skin disorders, such as psoriasis, alopecia areata, and allergic diseases, but has not been extensively studied in patients with chronic eczema. Objective. To evaluate the efficacy and safety of oral compound glycyrrhizin (OCG) plus topical corticosteroid (TCS) in adults with chronic eczema. Methods. This was a multicenter, randomized, double-blind, placebo-controlled study in patients with chronic eczema (n = 199). Randomized participants from 6 centers in China received either 75 mg OCG capsules or placebo capsules three times a day and TCS (i.e., 0.1% mometasone furoate ointment) once a day for 28 days. Efficacy was determined by analyzing the mean change from the baseline using standardized measures including the Investigator’s Global Assessment (IGA) score, Eczema Area and Severity Index (EASI), and the visual analogue scale score (VAS) of itching. Results. Decreases in absolute EASI were significantly greater in the OCG-treated group versus placebo on day 14 (−3.41 ± 1.41 vs. −2.71 ± 1.25, P<0.001) and day 28 (−7.39 ± 1.71 vs. −6.64 ± 1.75, P=0.003). OCG-treated patients also saw greater benefit in other EASI metrics including EASI-50 (96.8% vs. 87.9%, P=0.021) and EASI-75 (47.9% vs. 21.2%, P<0.001) on day 28 compared with placebo. The absolute IGA score reductions were also significantly greater in the OCG group than the placebo (all P<0.05). In addition, proportions of patients who achieve clear (0) IGA scores or almost clear (1) IGA scores were significantly higher in the treated group than placebo on day 14 (22.8% vs. 6.2%, P=0.001) and day 28 (93.5% vs. 79.4%, P=0.005). Moreover, the proportions of patients with reduced pruritus were significantly greater in the treated group than placebo on day 28 (94.7% vs. 83.8%, P=0.016) and eczema recurrence was notably less in the OCG group versus placebo (3.19% vs. 12.12%, P=0.021). Eleven patients experienced adverse events, but there was no significant difference in the proportion of patients affected (3.0% vs. 8.5%, P>0.05). The most common adverse events were edema of both lower limbs. Conclusion. For adults with chronic eczema, OCG capsules combined with TCS is an effective and well-tolerated treatment, suggesting that OCG may be a useful nonsteroidal agent with an additional effect for the treatment of chronic eczema by TCS.

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Section: Discussionsupporting

confidence: 49%

A Multicenter, Randomized, Double‐Blind, Placebo‐Controlled Study of Compound Glycyrrhizin Capsules Combined with a Topical Corticosteroid in Adults with Chronic Eczema

Mei

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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“…Therefore, hypoalbuminemia may be an important risk factor for PsA. Indeed, hypoalbuminemia has been identified as a risk factor in patients receiving yokukansan, which contains 1.5 g of licorice daily (49), as well as in other case series (50,51).…”

Section: Distributionmentioning

confidence: 99%

“…When bile excretion of GA3S is suppressed due to Mrp2 dysfunction (Figure 2), GA3S is transferred into the blood circulation. We have previously highlighted the involvement of Mrp2 in the biliary excretion of GL metabolites in rats (27,34,35) and possibly in humans (50,51). GL metabolites significantly accumulate in the EHBR (27,34,35).…”

Section: Excretionmentioning

confidence: 99%

Clinical Risk Factors of Licorice-Induced Pseudoaldosteronism Based on Glycyrrhizin-Metabolite Concentrations: A Narrative Review

et al. 2021

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Licorice, the dried root or stolon of Glycyrrhiza glabra or G. ularensis, is commonly used worldwide as a food sweetener or crude drug. Its major ingredient is glycyrrhizin. Hypokalemia or pseudoaldosteronism (PsA) is one of the most frequent side effects of licorice intake. Glycyrrhizin metabolites inhibit type 2 11β-hydroxysteroid dehydrogenase (11βHSD2), which decomposes cortisol into inactive cortisone in the distal nephron, thereby inducing mineralocorticoid receptor activity. Among the several reported glycyrrhizin-metabolites, 18β-glycyrrhetyl-3-O-sulfate is the major compound found in humans after licorice consumption, followed by glycyrrhetinic acid. These metabolites are highly bound to albumin in blood circulation and are predominantly excreted into bile via multidrug resistance-associated protein 2 (Mrp2). High dosage and long-term use of licorice are constitutional risk factors for PsA. Orally administered glycyrrhizin is effectively hydrolyzed to glycyrrhetinic acid by the intestinal bacteria in constipated patients, which enhances the bioavailability of glycyrrhizin metabolites. Under hypoalbuminemic conditions, the unbound metabolite fractions can reach 11βHSD2 at the distal nephron. Hyper direct-bilirubin could be a surrogate marker of Mrp2 dysfunction, which results in metabolite accumulation. Older age is associated with reduced 11βHSD2 function, and several concomitant medications, such as diuretics, have been reported to affect the phenotype. This review summarizes several factors related to licorice-induced PsA, including daily dosage, long-term use, constipation, hypoalbuminemia, hyper direct-bilirubin, older age, and concomitant medications.

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“…Therefore, when using Kampo medicines containing licorice, it may be possible to diagnose the predisposition to develop pseudoaldosteronism by detecting compound 3 in blood or urine at an early stage. In addition, GA cannot be transferred to renal tubular epithelial cells because the most of GA is bound to albumin in the blood, but during hypoalbuminemia, the concentration of free GA may increases and transport into tubular cells by passive diffusion to inhibit 11βHSD2 [19,20]. On the other hand, the concentration of urinary compound 3 in patient samples was lower than that in blood concentration [17].…”

Section: Discussionmentioning

confidence: 99%

Exploration for the real causative agents of licorice-induced pseudoaldosteronism

Makino

2021

J Nat Med

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I investigated the causative agents of licorice-induced pseudoaldosteronism, which is a frequent side effect of Japanese traditional Kampo medicines. Glycyrrhizin (GL), the main ingredient of licorice, is absorbed after being metabolized to glycyrrhetinic acid (GA) by intestinal bacteria, and then metabolized in liver to 3-monoglucuronyl-glycyrrhetinic acid (3MGA). In normal condition, 3MGA is excreted into bile via a multidrug resistance-related protein (Mrp) 2, therefore, 3MGA does not appear in blood circulation. However, under the dysfunction of Mrp2, 3MGA appears in the blood circulation and is excreted into the urine by not glomerular filtration but tubular secretion via organic anion transporter (OAT) 1 and 3. At this time, 3MGA inhibits type 2 11β-hydroxysteroid dehydrogenase (11βHSD2) in tubular cells to cause pseudoaldosteronism. Since GA is not the substrates of these transporters, GA cannot inhibit 11βHSD2 in tubular cells. Therefore, it was considered that 3MGA was the causative agents of licorice-induced pseudoaldosteronism. After that, I isolated and identified three other GL metabolites, 22α-hydroxy-18β-glycyrrhetyl-3-O-sulfate-30-glucuronide (1), 22α-hydroxy-18β-glycyrrhetyl-3-O-sulfate (2), and 18β-glycyrrhetyl-3-O-sulfate (3) from the urine of Mrp2-deficient rats orally treated with GA, and found that their blood and urinary concentrations were much higher than 3MGA and that their pharmacokinetic behaviors were similar to 3MGA. 3MGA was not detected in the blood of patients with pseudoaldosteronism who developed rhabdomyolysis due to licorice, and compound 3 was detected at a high concentration. In addition, a multicenter retrospective study was conducted using the serum and urine of 97 patients who took Kampo medicines containing licorice. Of a total of 97 patients, 67 detected GA in the serum (median 122 nM, 5 nM–1.8 µM) and 68 detected compound 3 (median 239 nM, 2 nM–4.2 µM), and there were no cases of detection of GL, 3MGA, compounds 1, and 2. High blood concentrations of compound 3 were associated with low plasma renin activity, plasma aldosterone levels, and serum potassium levels. It is highly probable that compound 3 is the true causative agent of pseudoaldosteronism.

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Risk factors associated with pseudoaldosteronism in patients with chronic hepatitis: A retrospective cohort study

Cited by 7 publications

References 21 publications

A Multicenter, Randomized, Double‐Blind, Placebo‐Controlled Study of Compound Glycyrrhizin Capsules Combined with a Topical Corticosteroid in Adults with Chronic Eczema

A Multicenter, Randomized, Double‐Blind, Placebo‐Controlled Study of Compound Glycyrrhizin Capsules Combined with a Topical Corticosteroid in Adults with Chronic Eczema

Clinical Risk Factors of Licorice-Induced Pseudoaldosteronism Based on Glycyrrhizin-Metabolite Concentrations: A Narrative Review

Exploration for the real causative agents of licorice-induced pseudoaldosteronism

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