A Case Of Severe Statin Induced Ileus

Multiple Muscle Melt: severe atorvastatin-induced hepatitis associated with rhabdomyolysis and leiomyolysis Authors Department of Gastroenterology and Hepatology, Monash Medical Centre, Clayton, Victoria, Australia Discussion

Introduction

HMG-CoA reductase inhibitor (statin) use is becoming more and more common. With an increasing breadth of indications, it has become the one of the top most prescribed classes in developed countries. In Australia, atorvastatin is the most commonly prescribed PBSsubsidised medication. Lipid lowering agents are the most commonly prescribed class. Hepatitis and myositis are both recognised side effects of statin therapy . Severe hepatitis, however, is less common. Visceral myopathy is also a very rare and perhaps under-recognised adverse event. We present an unusual case of both paralytic ileus and urinary retention associated with severe rhabdomyolysis with diaphragmatic involvement and hepatitis after an increase in dose of atorvastatin.

Case Report A 51 year old man with known alcohol abuse was admitted with a 5 day history of jaundice without abdominal pain, fevers or rigors on a background of generalised myalgia and lethargy, with no associated bladder or bowel dysfunction. His past history included alcoholic pancreatitis , hypertension and hyperlipidaemia. The myalgia corresponded to a change in dose of atorvastatin from 20mg to 40mg daily. The patient was also taking rabeprazole 20mg twice daily, candesartan 16mg daily and thiamine 100mg daily. Nil other substances including herbal supplements or illicit drugs were taken. Examination revealed jaundice, non-tender hepatomegaly, no evidence of decompensation or stigmata of chronic liver disease. Mild proximal muscle weakness limiting ambulation to 10m was also noted. There were no other abnormal neurological signs. His cardiorespiratory findings were unremarkable.

MRI of thighs showing T2 hyperintensity

Within 24 hours of admission, he developed severe muscle weakness, with a pronounced proximal emphasis. Neck flexor and proximal arm muscles were weak at MRC Grade 3/5, and hip flexor, gluteal and quadriceps groups had 2/5 weakness. A creatinine kinase (CK) done at this time was found to be elevated at 9923IU/ml. Atorvastatin was ceased, but weakness and CK increased over the next three days. He was bed-bound and unable to move his limbs, head or trunk against gravity. Vital capacity decreased. Two days after admission, he went into acute urinary retention of 831mL. MRI showed T2 signal change in gluteal, thigh adductor and hamstring muscle groups (Figure 1). A myositic screen was negative. Histopathological evaluation of a percutaneous vastus lateralis muscle biopsy revealed a diffuse toxic rhabdomyolysis affecting all muscle layers consistent with a drug-related myositis . It appeared he was starting to have diaphragmatic involvement and oxygen saturations also decreased. Due to these concerns, he was commenced on empiric intravenous hydrocortisone (100mg IV qid) on day 3. 5 days after admission, he developed acute severe abdominal distension associated with nausea, vomiting and absolute constipation. An abdominal X-ray revealed grossly dilated large and small bowel loops with no transition point (figure 3) and a gastrograffin followthrough confirmed no mechanical no obstruction. On sigmoidoscopy an irregular, oedematous, congested mucosa was seen, however no cause was found for this abnormality, nor any mass lesion. Ileus continued and he once again underwent emergent decompression, this time with colonoscopy which was aborted due to the high risk of perforation. Unfortunately, he developed a transverse colon perforation postprocedure and proceeded to laparotomy with formation of defunctioning colostomy.

Abdominal Xray on Day 8 of admission showing ileus

Our patient also had an extremely aggressive form of progressive myositis involving not only axial muscles but also his muscles of respiration. Similarly to liver impairment, factors that increase the likelihood of myopathy include co-administration of drugs metabolised by subgroup CYP3A4 as well as fibrates. From the experience in treating other myopathies, steroids show normalisation of creatine kinase over time, however efficacy is best shown in dermatomyositis and polymyositis . Myositis involving both skeletal and smooth muscle has been documented in inflammatory myopathies previously in several case studies. Smooth muscle myositis associated with statin therapy however is very rare, with only a few case studies noted in the literature. These case studies suggest that it is associated with more severe hepatitis or rhabdomyolysis (figure 1). Our respiratory function tests suggested diaphragmatic involvement which has not been previously described. Though no definitive histology was available, the severe ileus which culminated in bowel perforation was suspected to have been caused by leiomyolysis. Bowel function improved concomitantly with recovery of skeletal muscle and liver function. There was no clinical evidence of peripheral or autonomic neuropathy. Other reports of intestinal pseudo-obstruction are scarce. One case occurred after the addition of cerivastatin to cyclosporine resulting in a paralytic ileus, rhabdomyolysis and severe hepatitis. Another case reports the addition of erythromycin to existing statin therapy, with subsequent multi-organ failure and ileus . In both these cases, combination therapy was the precipitant. Our case illustrates that dose escalation can also be the trigger. Urinary retention postulated to be due to bladder smooth muscle involvement has been described previously. Our case, however, shows that this can occur along with severe skeletal and bowel myositis. Whether urodynamics in the acute setting is helpful remains unclear.

Conclusion

In the setting of a recently introduced or dose escalated statin therapy, severe skeletal myositis should prompt the treating clinician to monitor respiratory status carefully, ideally with daily vital capacities. Monitoring of bladder and bowel function is also necessary to look for any smooth muscle involvement and the use of steroids may aid in both skeletal and smooth muscle recovery.