Dear Editors,
We read with great interest the recently published article “Subnormal Serum Liver Enzyme Levels: A Review of Pathophysiology and Clinical Significance” by Youssef and colleagues.1 While much attention is given to elevations of liver enzymes, the authors highlight clinically important, often unrecognized reasons leading to low liver enzyme levels. For example, chronic kidney disease was cited as a cause of low serum aspartate aminotransferase (AST) proportional to the progression of the disease, but the cause(s) are not well defined. Little is known about the possible influence of nephrotic syndrome (NS) on liver enzymes. NS is a kidney disorder characterized by increased permeability of the glomerular capillary wall, high-grade proteinuria (≥3.5 g/day), hypoalbuminemia (serum albumin ≤ 3.0 g/dL), hyperlipidemia, and edema. The massive urinary losses of many important plasma proteins due to NS (e.g., albumin, thyroid binding globulin, transferrin, vitamin D-binding protein, coagulation regulatory proteins) lead to decreased circulating concentrations in the blood and consequent metabolic, biochemical, and endocrine abnormalities such as hypothyroidism, vitamin D deficiency, and hypercoagulability.2 We evaluated if NS might be another potential cause of subnormal liver enzymes, possibly due to excessive urinary losses of these enzymes or other factors. Subnormal liver enzyme tests could potentially mask clinically relevant clues to coexisting liver diseases that can cause NS (e.g., viral hepatitis3,4), are associated with NS (e.g., autoimmune hepatitis5,6), or result from hepatotoxicity from drugs used in the treatment of NS (e.g., calcineurin inhibitors, HMG-CoA reductase inhibitors). To test this hypothesis, we identified patients with a history of primary NS who had paired liver enzyme tests (analyzed in the same clinical laboratory) during active NS (ANS) and during clinical remission of NS (defined as proteinuria <350 mg/day). This allows a unique comparison of intra-individual changes in liver enzymes during two contrasting disease states, with nephrotic patients serving as their own controls. Medications known to impact liver tests (e.g., statins) had to remain unchanged at the two distinct clinical time points for patients to be included in the analysis. Of 52 patients identified with paired samples, most (71%) had primary membranous nephropathy as the cause of NS. One patient (2%) had hepatitis C infection, five (9.6%) had hypertension, and one (2%) had diabetes mellitus. Median proteinuria during ANS and remission was 6.39 g/g (4.39–10.18) and 0.19 (0.1–0.32), respectively (p < 0.0001). Median serum albumin during ANS was lower than in remission (p < 0.0001) (Table 1). Serum creatinine did not differ during ANS versus remission (p = 0.18). Median total bilirubin and alkaline phosphatase were lower during ANS compared to remission: 0.25 mg/dL (0.2–0.32) vs. 0.44 (0.37–0.6) (p < 0.0001) and 61.5 U/L (49–74) vs. 65.5 (57.7–85) (p = 0.005), respectively. No differences were found in the median direct bilirubin (p = 0.07) or in ALT (p = 0.88) and AST (p = 0.1) during ANS and remission. Median platelet count was higher (p = 0.0001) during ANS. Expectedly, LDL, HDL, total cholesterol, and triglycerides were elevated (p < 0.001) during ANS. We did not find a correlation between liver enzymes and NS-related dyslipidemia (Fig. 1), despite the known role of the liver in contributing to excess cholesterol biosynthesis during NS and the known contribution of prolonged dyslipidemia to the development of metabolic dysfunction-associated steatotic liver disease in the general population.
Table 1Biochemical Lab results during active nephrotic syndrome and remission
| Number of patients* | Active nephrotic syndrome | Remission | P-value |
|---|
| Urine protein/creatinine ratio (g/g) | 52 (100%) | 6.39 (4.39–10.18) | 0.19 (0.1–0.32) | <0.0001 |
| Serum albumin (g/dL) | 52 (100%) | 2.75 (2.37–3.2) | 4 (3.8–4.2) | <0.0001 |
| Serum creatinine (mg/dL) | 52 (100%) | 1.17 (1.02–1.49) | 1.16 (0.88- 1.46) | 0.18 |
| AST (U/L) | 52 (100%) | 21 (18–30.5) | 20.5 (17–25.2) | 0.88 |
| ALT (U/L) | 52 (100%) | 20.5 (15–27.5) | 20 (15–26.2) | 0.96 |
| ALP (U/L) | 60 (100%) | 61.5 (49–74) | 65.5 (57.7–85) | 0.005 |
| Total bilirubin (mg/dL) | 60 (100%) | 0.2 (0.2–0.32) | 0.44 (0.37–0.6) | <0.0001 |
| Direct bilirubin (mg/dL) | 60 (100%) | 0.2 (0.1–0.2) | 0.2 (0.2–0.2) | 0.07 |
| Total cholesterol (mg/dL) | 45 (86.5%) | 230 (208.5–321.7) | 176 (144–209) | <0.0001 |
| LDL (mg/dL) | 45 (86.5%) | 120.5 (95.5–211.5) | 89 (65–119) | 0.0002 |
| HDL (mg/dL) | 45 (86.5%) | 67.5 (51.7–80.2) | 56 (43–66) | 0.0001 |
| Triglycerides (mg/dL) | 45 (86.5%) | 153.5 (118.7–210) | 120 (67–165) | 0.0024 |
| Platelet x100/mcL | 51 (98%) | 250.5 (217–332.2) | 238 (195.5–284) | 0.0001 |
We acknowledge the limitations of this study. The population size was small, and the majority had kidney-limited disease due to primary membranous nephropathy with few comorbidities. This allowed for a better assessment of the impact of proteinuria alone on liver enzymes. However, these findings require validation in larger studies that include patients with different causes of nephrotic syndrome, including patients with hepatitis-associated nephrotic syndrome.
In summary, the presence of high-grade proteinuria does not appear to lead to subnormal serum liver enzyme levels. Both total bilirubin and ALP were lower during ANS compared to remission; however, the changes were minor and not clinically significant. The more hepatic-specific direct bilirubin revealed no difference, nor did ALT and AST. However, the absence of biochemical liver abnormalities may not exclude the presence of indolent liver disease, and appropriate serologic workup, radiologic imaging, and possibly liver biopsy should be considered if suspected.
Declarations
Funding
This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.
Conflict of interest
The authors have no conflict of interests related to this publication.
Authors’ contributions
DY: conceptualization, methodology, data curation, investigation, formal analysis writing original draft, writing-review & editing, visualization. AH: methodology, software, validation, formal analysis, data curation, investigation, writing-review & editing, visualization. LH: data curation, resources, investigation, writing-review and editing. TH: conceptualization, investigation, resources, supervision, funding acquisition. MW: investigation, resources, data curation, methodology, writing-review &editing, supervision, validation, project administration, funding acquisition.