Case Summary Of A Woman With Intermittent Creatine Kinase And Transaminase Elevation With Diabetes Mellitus Syndrome

Objective:To present and discuss possible etiology of a case of polycystic ovary syndrome and skeletal pain with intermittent elevation of creatine kinase and transaminase,followed by development of diabetes mellitus(DM).Methods:We retrospectively retrieved the clinical data of a patient with intermittent creatine kinase and transaminase elevation with diabetes mellitus syndrome who was successively admitted to our hospital several times between 2013 and 2022,including symptoms,signs,laboratory results,imaging,genetic analysis,management and follow-up.Case Report:The patient was a young woman of 35 years old.Nine years ago,the patient began to experienced intermittent lower limb myalgia with an elevation of creatine kinase(CK)and transaminase and irregular menstruation.At that time her weight was 59 kg(BMI 22.5 kg/m~2).The myalgia of lower limbs was more frequent after cold or fatigue.The myalgia lasted for 2-4 days each time.The CK and transaminase were increased at the onset,and the highest CK was 3309 U/L;after remission of symptoms,CK returned to normal,without muscle weakness or paresthesia in both lower limbs.Muscle biopsy showed no obvious abnormality;Self-reported symptoms were improved after taking oxycodone acetaminophen.The patient also was found to have mildly elevated transaminase level accompanied with fatty liver,hyperlipemia,she denied intake of statins or other special drugs,and hepatitis virus markers were negative.Menstruation is rare,with a period of 40-60 days,and menstruation was treated with Chinese herbs(details are unknown).Seven years ago,an inpatient physical examination found acanthosis nigricans in the neck,accompanied by significant insulin resistance,impaired glucose tolerance,high testosterone,b-mode ultrasonography showed polycystic changes of the ovaries,she was diagnosed with“Polycystic ovary syndrome,impaired glucose tolerance,insulin resistance”,after progesterone the metformin and pioglitazone treatment,her menstruation returned to normal,and the woman recalled her memory began to decline in the same year,especially in the memory of recent events.About six years ago,the patient stopped taking pioglitazone,and metformin was continued orally,and her blood sugar level reached the level of diabetes mellitus without diabetes symptoms.Five years ago,she was admitted again,and polycystic ovary features were not found by the b-ultrasound,and her menses resumed monthly.Two years ago,her workup revealed glutamic acid decarboxylase antibody(GADA)positive and insulin autoantibody(IAA)negative.Her blood glucose control improved significantly after switching to empagliflozin and pioglitazone.After adding inosine tablets,the transaminase level was significantly improved,and an occasional calf tremor was observed recently.As past history,she received a two-year"stem cell"treatment at another hospital six years ago(details unknown).The patient reported that the degree and frequency of myalgia were relieved to somewhat extent.On physical examination after readmission on April 1,2022,her blood pressure was 104/90 mm Hg,height 162 cm,bodyweight 80 Kg,abdominal circumference 95 cm,hip circumference 105 cm,BMI 30.48 Kg/m~2,her development was normal with obesity,reasonable Q&A.the cardiopulmonary and abdomen were nonremarkable.No swelling or tenderness of the lower limbs was detected.Muscle strength was 5 grade,the muscle tension of the limbs was as expected,knee reflex were symmetrical,and the rest nervous system was negative.Her GADA was still positive.A second-generation exome sequencing was ordered,and three gene mutations were detected as PDX1(exon2:c.697G>A:p.E233K,of unknown significance),BLM(exon18:c.3478t>C:p.Y1160H,of unknown significance)and ATP7B(exon8:c.2297C>T:p.T766M,of suspected pathogenesis).Bloom syndrome(BLM)and Wilson disease(ATP7B)are autosomal recessive.The mutation of the PDX-1 gene was supposed to be nonsense by ACMG guideline,and whether this mutation is associated with insulin resistance and,subsequently,diabetes needs to be further clarified as the patient was also found GADA positive in the year 2020.Although a putative Wilson syndrome ATP7B mutation on one allele was found,we could not exclude this patient should contain a critical intron regulatory mutation.Because there was no clue in this patient for her intermittent skeletal pain and elevation of creatine kinase,therefore,blood copper and ceruloplasmin were ordered,the result showed that her serum copper was 17.93 umol/L at the high reference range(12.56-23.55 umol/L)and ceruloplasmin0.25 g/L at the low reference range(0.2-0.6 g/L),so the disorder of copper metabolism was suspected.Diagnose of latent autoimmune diabetes in adults(LADA)and suspected Wilson’s disease were made.Pioglitazone 30mg once a day and empagliflozin10mg once a day were continued for her glycemic control and inosine tablets 0.4 g three times a day as a possible relief for her creatine kinase.At the last follow-up,2022.9.13,fasting blood glucose:4.97 mmol/L;fasting insulin:8.89mu/L.Her menses is normal,and the degree and frequency of myalgia improved,but it still exists currently.During the onset of myalgia,significant elevation of CK was still observed,but the peak value of CK was lower than before.She is currently closely followed,monitoring of blood copper,ceruloplasmin and urine copper were planned;once the disorder of copper metabolism is confirmed,copper depletion therapy will be implemented to reduce the damage to tissues and organs caused by copper deposition as soon as possible.Conclusion:1.LADA is a subtype of type 1 diabetes mellitus and a slowly progressive autoimmune diabetes mellitus with insidious onset in adults in the form of clinical manifestations of type 2 diabetes mellitus(T2MD),which is difficult to distinguish from T2MD in the early stages,especially in the case of low titers of GADA antibodies,the clinical manifestation is more similar to T2MD.Due to the immune-mediated slow destruction of pancreatic isletβcells,β-cell function diminishes as the disease progresses and eventually fails.This patient was successfully managed by pioglitazone and empagliflozin because pioglitazone increased the body weight into the range of obesity in this patient,GLP-1RA might be more beneficial.2.Wilson’s disease is a genetic disorder of copper metabolism with high heterogeneity in genotype and phenotype and has a wide range of clinical manifestations.The clinical manifestations of the patients included muscle injury,liver injury,endocrine disorder and neuropsychiatric disorder.The heterozygous mutation of the ATP7B gene was found by gene detection,which may be helpful for the diagnosis of Wilson’s disease.Further analysis for additional mutation with whole genome sequencing might be helpful in final excluding or accepting the diagnosis of Wilson syndrome in this woman.