Thyrotoxicosis presenting with rapidly progressive severe systemic edema and tense ascites in the setting of dynamic systolic function

*Michael Marchese, *1,2 Mandeep Sidhu 1,2, Joseph Sacco 1,2 and Subhashini Yaturu1,2 1Albany Medical College; 2Stratton VA Medical Center, Albany, New York

SAT- 0466

1. About 6% of patients with hyperthyroidism developed CHF compared to 5.6 per 100,000 general populations.

2. In hyperthyroid patients mortality also increases by 20% and the major causes of death are cardiac in nature.

3. Triidothyronine (T3) is an active thyroid hormone that mediates the expression of many cardiac genes (myosin, sarcoplasmic reticulum and cell membrane) leading to a hyperdynamic circulatory state and in turn is responsible for the well-recognized cardiovascular manifestations of hyperthyroidism including palpitations, tachycardia, dyspnea on exertion and atrial fibrillation.

4. It can consequently exacerbate pre-existing cardiac disease or cause de novo cardiovascular abnormalities such as high and low output heart failure.

5. Cardiac manifestations are the main reason for hospital visits.

6. Pulmonary hypertension is said to be a common but clinically unrecognized condition with a frequency of 47% among hyperthyroid patients with asymptomatic pulmonary hypertension.

7. Chylous ascites can be a manifestation in hyperthyroidism as noted in few case reports.

8. We present an unusual case of Graves’ disease with tense ascites and high out-put heart failure.

HPI: 64- year old male Veteran referred to Endocrinology clinic for evaluation of hyperthyroidism.

• Initial presentation to patient’s primary care provider included: unintentional 15lb. weight loss over 6 months duration, increasing abdominal girth of 2 months duration, pain associated with worsening dyspnea on exertion, diarrhea, rapidly progressive lower extremity edema, tense ascites of 2 weeks duration.

• Initial work up by PCP: CBC and CMP normal, hepatitis panel (table 2) and thyroid panel with antibodies (Table 1). CT chest, abdomen and pelvis revealed massive ascites, normal liver parenchyma with no evidence of discrete solid or cystic lesions or dilated intrahepatic bile ducts

Past medical history: Significant for coronary artery disease post MI and subsequent percutaneous stent placement in 1999, hypertension and hyperlipidemia.

Social history: Former smoker (10 pack years) and occasional alcohol use of no more than 2 drinks per week

Family history No thyroid disease.

Physical exam at Endocrinology Visit: Patient was tachycardia with heart rate of 110bpm; tachypnea at a rate of 30/min. No exophthalmos. Large soft thyroid that was about twice normal size with a bruit, increased jugular venous pulse. Grade 2 systolic ejection murmur heard best at the sternal border and decreased breath sounds at the base of the lungs. Tense ascites with prominent anterior abdominal veins. 3+ edema of BL lower extremities and fine tremor noted on outstretched hands

• Patient was immediately hospitalized as the physical examination findings were consistent with high output heart failure from uncontrolled hyperthyroidism.

Admit Lab Work: Shown in laboratory data section

Admit Imaging: EKG sinus tachycardia. Chest X-ray (Figure 3) bilateral pleural effusions and mild cardiomegaly. Thyroid scan could not be done as he had high iodine load from CT scans with contrast.

• Hyperthyroidism is known to affect the cardiovascular system leading to a hyperdynamic circulatory state. (9)

• One common but unrecognized condition is pulmonary HTN, exact mechanism unclear.

• Right heart failure can be a direct result of left heart failure, Tricuspid regurgitation or pulmonary HTN.

• The right ventricle is primarily a volume chamber and not adapted to handling increased workload, which leads to dilation of the RV and Hypertrophy which can produce passive congestion of the liver and peripheral edema (10)

• In out patient thyroid uptake was not completed, but suppressed TSH and elevated TSI confirmed the diagnosis of Grave’s disease

• PASP 53mmHg on TTE and elevated right hearth catherization pressures where consistent with 2011 European Society of Cardiology guidelines for diagnosis of Pulmonary Hypertension

• During our patients hyperdynamic state his pulmonary HTN and right heart strain lead to his initial unique presentation of tense ascites with near normal transaminase.

• To our knowledge this is the first case of tense ascites as the initial presentation of Graves’ disease.

• Patient was well controlled with PTU, prior to each hospital discharge he was switched to methimazole, each time leading to relapse of symptoms raising concern for methimazole resistance.

• Possible mechanisms for methimazole resistance are drug malabsorption, accelerated drug removal from serum or the existence of a protein that binds to methimazole rendering it inactive.

1) Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J Med 2001; 344:501-9. 2) Huang MJ, Liaw YF 1995. Clinical Associations between thyroid and liver diseases. J Gastroenterol Hepatol 10:344-350. 3) Ertek S, Cicero A. Hyperthyroidism and cardiovascular complications a narrative reviews on the basis of pathophysiology. Arch Med Sci 2013; 9,5: 944-956. 4) Siu CW, Yeung CY, Lau CP, Kung AWC, Tse HF. Incidence, clinical characteristics and outcome of congestive heart failure as the initial presentation in patients with primary hyperthyroidism. Heart 2007; 93:483-487. 5) Brandt F, Green A, Hegedus L, Brix TH. A critical review and meta-analysis of the association between overt hyperthyroidism and mortality. Eur J endocrinol 2011; 165:491-7. 6) Siu CW, Zhang XH, Yung C, Kung AWC, Lau CP, Tse HF. Hemodynamic changes in hyperthyroidism-related pulmonary hypertension: A prospective Echocardiographic study. J Clin Endocrinol Metab 92:1736-1742, 2007. 7) Montani et al. Pulmonary Artery Hypertension: Review. Orphanet Journal of Rare diseases 2013,8:97. 8) Baptista A, et al. Pulmonary hypertension, heart failure and hyperthyroidism: A case report. Rev Port Cardiol 2013; 32(3): 253-256. 9) Kubota S, Amino N, Matsumoto Y, et al. Serial changes in liver function test in patients with thyrotoxicosis induced by Graves’ disease and painless thyroiditis. Thyroid. 2008; 18:283-287. 9) Thompson Jr P, Strum D, Boehm T, Wartofsky L. Abnormalities of liver function tests in thyrotoxicosis. Mil Med 1978; 143:548-51. 10) Doran GR. Serum enzyme disturbances in thyrotoxicosis and myxedema. J R Soc Med 1978;71:189-94. 11) Janda S, Shahidi N, Gin K, et al. Diagnostic accuracy of echocardiography for pulmonary hypertension: a systemic review and meta-analysis. Heart 2011; 97:612-22. 12) J H Li, R.E. Safford, J.F. Aduen, M.G. Heckman, J.E. Crook, and C.D. Burger “Pulmonary Hypertension and thyroid disease,” Chest 2007, Vol 132(3) 793-797. 13) Cooper DS. 1991. Treatment of thyrotoxicosis. In: Braverman LE, Utiger RD, Werner and Ingbars the Thyroid: A fundamental and clinical text. 6th ed. J.B. Lippincott Company, Philadelphia: 887-916.

Hospital Course:

• Therapeutic paracentesis completed. Propothyouracil 100 mg PO TID and propranalol 20mg PO Q6 hours with parameters to increase to reach a goal heart rate less than 90 was initiated. Patient was diuresed with furosemide and amlodipine was discontinued for fear of worsening edema. Echocardiogram(Table 3) revealed normal right and left ventricular function with normal wall motion. Left ventricular ejection fracture was 55%, moderate tricuspid regurgitation and pulmonary artery systolic pressures of 53 mm. of Hg (<28). Patient improved and was switched from PTU to methimazole prior to discharge.

• He was readmitted to the hospital on methimazole and had a therapeutic abdominal paracentesis. Serum albumin to ascites gradient was 0.6g/dL however patient was on diuretics. When stable, he was discharged on methimazole. With each discharge (thrice) and change to methimazole he was readmitted for re accumulation of his ascites, as a result he was maintained on PTU. Gradually the ascites resolved on PTU alone.

• Thyroid ultrasound was subsequently ordered and patient was found to have bi-lobed enlargement with increased blood flow.

• Right and left heart catheterization without angiography (Table 4.) revealed normal left sided pressures with elevated right heart pressures. Consistent with high cardiac output and pulmonary hypertension.

• Given large PTU requirements (200 mg tid) and fear of recurrence of ascites, he was treated with radioactive iodine ablation 29.6mCi of I-123 treatment while on propothyouracil.

• Complete resolution of the ascites occurred with improvement of thyroid function test.(Table 1)

• The plan is to repeat radioactive iodine therapy in the future.

Blood work Reference - 24 - 6 Admit +1 +3 +6 +16

TSH (uIU/mL) 0.35-5.50 1.09 0.6 0.00 0.00 0.00 0.03 0.02

Free T4 (ng/dL) 0.7-1.5 0.96 3.39 0.77 3.41 1.61 0.87

T3 (ng/dL) 60-150 334.8

Free T3 (ng/dL) 2.0-4.4 5.2 5.3 3.4 3.4

Thyroid Stimulating IG (%) 0-139 356

Thyroid peroxidase Ab (IU/mL) 0-34 123

Anti-Thyroglobulin (IU/mL) 0-40 <20

TSH Receptor Ab (IU/L) 0.00-1.75 47

TSH = Thyroid Stimulating Hormone; Free T4 = Thyroxine; T3 = Triiodothyroxine

Treatmentwith29.6mCi

Table 1. Thyroid Function Panel

Blood work Reference Months from Admission

- 24 - 6 Admit +1 +3 +6 +16

Protein (g/dL) 6.2-7.8 7.4 7.2 6.7 8.1 7.3 8.0 7.5

Albumin (g/dL) 3.4-4.5 4.1 4.0 3.3 3.1 2.5 2.7 4.1

T. Bili (mg/dL) 0.1-1.0 0.6 0.5 1.7 0.6 0.6 0.5 0.6

Alk Phos (units/L) 50-136 93 86 178 141 160 122 154

AST (units/L) 12-34 21 30 27 19 24 15 19

ALT (units/L) 10-55 15 19 12 9 13 9 21

Hep C Ab – EIA Negative Neg

Iron (mcg/dL) 35-150 21

UIBC (mcg/dL) 140-326 171

Iron Saturation (%) 17-44 10.9

Ferritin (ng/mL) 11-434 338.4

Alpha 1Antitrypsin (mg/dL) 90-200 268

BNP (pg/mL) <100 630

Table 2. Additional Blood Work

Treatmentwith29.6mCi

Figure 1. Thyroid Scan

Figure 2. Liver Ultrasound

Normal liver parenchyma with no evidence of discrete solid or cystic lesions or dilated intrahepatic bile ducts

Table 3. Echocardiogram

Left Ventricle Normal size, wall thickness and motion. NL sys. function. EF >55%

Atria Left atrium is mod. dilated. Right atrium is mod. to severely dilated

Mitral Valve Leaflets normal

Tricuspid Valve Valve normal. Mild to mod. TR. RVSP elevated 40-50mmHg

Aortic Valve Trileaflet, opens well. Mild aortic stenosis. Mild to mod AR

Pulmonic Valve Valves thin and pliable. PASP 53mmHg

Great Vessels Mild aortic root dilation

Biatrial enlargement with normal right ventricular systolic function and left ventricular

dimension. Estimated LVEF >55%. Trileaflet aortic valve with mild to moderate AI, Ascending

aorta 4.1cm and moderate tricuspid regurgitation. Estimated PASP 53mmHg

Table 4. Cardiac Catheterization

Left Heart Catheterization Right Heart Catheterization

Pressures (mm/Hg)

Reference Pressures (mmHg) Reference

Aorta 108/55 (90-140/60-90) RAmean 20(é) (1-8)

LVSP 120 (100-140) RV 45/20(é) (15-30/1-8)

LVEDP 28(é) (4-12) PA 45/13(é) (15-30/1-8)

Aor cValveStenosis

None None PCWP 21(é) (4-12)

C.O.andC.I. Values References

Cardiacoutput(L/min) 10.23(é) (4-8)

CardiacIndex(L/min/m2) 4.92(é) (2.5-4.0)

Satura on(%)

ArterialSatura on 96% (95-100)

Mixedvenoussat. 70% (65-70)

VascularResistance

Pulm.VascResistance 0.8

Syst.Vasc.Resistance 469

Aor cValveStudy

Peakgradient(mmHg) 12

MeanGradient(mmHg) 9

Valvearea(cm2) 4.00 2.5-4.5

Valvestenosis No No

Hemodynamics consistent with high output heart failure and elevated right heart pressures from pulmonary hypertension