High-Intensity Statin Therapy and Associated Rhabdomyolysis in Chronic Liver Disease: A Case Report and Review of Literature

Current literature suggests an increased incidence of rhabdomyolysis in patients with chronic liver disease (CLD) compared to the general population. We present a case of a 60-year-old female with a history of non-alcoholic fatty liver disease and cirrhosis who developed rhabdomyolysis and acute kidney injury after starting high-intensity atorvastatin therapy. This case highlights the potential risks associated with high-intensity statin therapy in patients with CLD, particularly those with advanced liver dysfunction, emphasizing the need for cautious prescribing and thorough risk-benefit assessment in this vulnerable patient population.


Introduction
Statins are the most prescribed lipid-lowering drugs in the world that have proven benefits in decreasing atherosclerotic cardiovascular diseases. High-intensity statin therapy is associated with a 55-60% reduction in LDL levels and a decrease in major adverse cardiovascular events [1]. Independent of reduction in LDL, statin may also be beneficial in various other diseases including chronic liver disease (CLD) due to its pleiotropic effects [2,3]. Though rhabdomyolysis is a known side effect of statin, its incidence is very low (about 0.1%) [1]. Given that most of these studies excluded individuals with liver disease in their studies, they cannot be generalized to individuals with CLD. There is literature that suggests an increased risk of muscle injury in this subset of patients [4][5][6]. With the emergence of this new literature, it is important for clinicians to look at its safety in this subset of patients.

Case Presentation
A 60-yrs-old female with a body mass index of 32.77 kg/m 2 , a history of non-alcohol fatty liver disease and cirrhosis (Child-Pugh C), paroxysmal atrial fibrillation, moderate mitral and aortic stenosis, and moderate aortic regurgitation presented to hospital with severe weakness in the bilateral upper and lower extremities especially proximal muscles and an episode of recent mechanical fall. Physical exam revealed ascites and follow-up labs were suggestive of acute kidney injury (AKI), with elevated bilirubin, AST, and mildly elevated ALT. Creatinine phosphokinase (CPK) was found to be 35,400 units/L. An initial diagnosis of rhabdomyolysis was established. Elevated AST was thought to be due to muscle injury. The initial set of labs and home medication are shown in the   Urinalysis showed muddy casts with high fractional excretion of sodium likely suggestive of intrinsic renal injury. The hepatorenal syndrome was considered differential but muddy casts in UA, current rhabdomyolysis, and lack of response to 2g/kg albumin infusion for two days were suggestive of acute tubular necrosis due to rhabdomyolysis. 25 days prior to hospital admission, she was placed on highintensity statin therapy (atorvastatin 80 mg) for microvascular ischemic changes seen on the CT head. Atorvastatin was discontinued on the second day of admission. Resuscitative IV fluids, dextrose, and bicarbonate drips were initiated and titrated to alkalinize the urine. CPK was initially up-trending but then started trending down after four days of continuous IV fluids and cessation of atorvastatin. Given the severity of the presentation and proximal weakness, she was also tested for autoimmune myopathies and statin-induced necrotizing rhabdomyolysis, the workup for which has been negative ( Table 2).  Over the course of the next few days, her CPK continued to trend down, and LFTs remained stable, but her renal function continued to worsen (Figure 1). After shared decision-making, considering her prior comorbidities including liver cirrhosis, the patient and family decided not to pursue dialysis. She was managed conservatively with albumin infusions and diuretics. Over the next few days, she developed type II myocardial infarction due to volume overload and disseminated intravascular coagulation. With the progressive decline, the family elected to pursue palliative care.

Discussion
Statins are well-studied lipid-lowering agents, and the incidence of serious muscle injuries along with rhabdomyolysis is reported as 0.1% [1]. Statin-associated rhabdomyolysis was first reported in 1988 in a cardiac transplant recipient taking lovastatin [7]. Since then, there were many studies on the propensity of these drugs that cause rhabdomyolysis, but most of these did not include patients with liver disease. Though the exact mechanism remains unknown, statins are believed to induce skeletal muscle necrosis likely secondary to a decrease in ubiquinone (coenzyme Q) [8]. Plasma levels, type (hydrophilic vs hydrophobic), dose and drug interactions, and pharmacokinetics [9,10] of statins can each affect the adverse events contributed by the medication. Statins like simvastatin (dose restricted to 40 mg), rosuvastatin (dose restricted to 80mg), pitavastatin (dose restricted to 4mg), and cerivastatin (recalled from the market) were either dose restricted or recalled from the market secondary to increased muscle-related adverse events [1].
Though the incidence of serious muscle injury is minimal in the general population, the incidence tremendously increases in individuals with CLD [4]. In LiverHope, a safety double-blind randomized clinical trial evaluated the safety of different doses of simvastatin along with rifampicin in patients with decompensated cirrhosis and found that 3 of 16 patients (19%) using simvastatin 40 mg + rifampicin 1200 mg developed rhabdomyolysis [5]. The BLEPS (bleeding prevention with simvastatin) trial evaluated the addition of simvastatin to standard therapy in patients with cirrhosis for preventing variceal rebleeding in which 2 of 69 patients (2.9%) on simvastatin developed rhabdomyolysis [6]. In a prospective uncontrolled study evaluating the safety of chronic simvastatin treatment in decompensated liver cirrhosis, 4 of 30 patients (13.3%) developed rhabdomyolysis [4]. This increased incidence of rhabdomyolysis compared to the general population is likely due to increased therapeutic concentration of statin secondary to altered pharmacokinetics in patients with liver disease [4]. Atorvastatin undergoes extensive first-pass metabolism with a bioavailability of around 14% and is dependent on hepatic clearance [11]. Though there are no studies looking at the pharmacokinetics of statin in Child-Pugh Class C patients, it is likely that the bioavailability is much higher in these patients owing to impaired pharmacokinetics.
A meta-analysis done by Kamal et al. showed that the use of statin in liver disease has mortality benefits [3], but most of the studies included in this meta-analysis are observational studies and patients belong to Child-Pugh Class A. This cannot be generalized to all patients with CLD and especially individuals with Child-Pugh Class C. In summary, patients with CLD may be at higher risk of serious muscle injury compared to the general population. Our patient had a CLD with Child-Pugh Class C. The use of high-intensity atorvastatin has led to rhabdomyolysis and AKI.
info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.