Hypothyroidism and muscular respiratory failure successfully treated with liothyronine.

ABSTRACT: After total thyroidectomy because of hyperthyroidism, hypothyroidism developed in a 78-year-old woman. Despite replacement therapy with levothyroxine sodium in continuously increasing doses, worsening hypothyroidism led to respiratory failure, necessitating artifical ventilation. The addition of liothyronine resulted in complete recovery. Impaired conversion of thyroxine to triiodothyronine by the dejodase was responsible for the manifestations of hypothyroidism.

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NEUROMUSCULAR affection of hypothyroidism usually involves the limb muscles. Affection of the respiratory muscles, leading to respiratory failure, is a rare manifestation of hypothyroidism. (1-4)

CASE REPORT

A 78-year-old woman had a history of resected ovarian dermoid cyst, diaphragmatic hernia, angiolipoma in the left kidney, recurrent anginal chest pain, multiple liver cysts, cysts in the right kidney, thrombocytopenia, and a multinodular goiter. In August 2000, ptosis and double vision developed, and in October dysphagia, hoarseness, and recurrent dyspnea also occurred. Thyroid function tests revealed hyperthyroidism (Table), and the patient had uneventful total thyroidectomy. Despite postoperative replacement therapy with levothyroxine (50 [micro]g/day), hypothyroidism developed (Table). The levothyroxine dosage was increased to 100 [micro]g/day in November, but symptoms worsened and included impaired visual acuity, exercise intolerance, increasing fatigability, dry skin, general weakness, general wasting, and weight loss attributed to dysphagia.

On admission to the hospital in December, results of thyroid function tests were normal. Videofluoroscopic investigation of swallowing (hospital day 2) showed slowed deglutition, slowed opening of the upper esophageal sphincter with damming of the bolus, continuous swallowing, and delayed opening of the cardia. Clinical neurologic investigation (day 5) revealed dysarthria and reduced deep tendon reflexes of the lower limbs. Cerebral magnetic resonance imaging (MRI) (day 8) showed periventricular leucaraiosis and a few hyperdense lesions in the frontotemporal and occipital white matter. Despite normal findings on acetylcholine receptor antibody tests, repetitive stimulation, and thoracic CT, myasthenia was suspected. Treatment with pyridostigmine (160 mg/day) was begun on day 14 without effect.

Because of acute respiratory failure due to muscle weakness (day 16), the patient had to be intubated and artificially ventilated. The pyridostigmine dosage was increased to 300 mg/day but still had no effect. From day 18, pyridostigmine was given intravenously (12 mg/day), again without effect. Hypothyroidism persisted (Table). Routine blood studies showed anemia, thrombocytopenia, monocytosis, slight hypoproteinemia, hypoalbuminemia, hyponatremia, and increased [gamma]-globulins (Table). Attempts of extubation were always unsuccessful after a few hours, since bradycardia and arterial hypotension repeatedly developed. Pyridostigmine therapy was discontinued on day 34.

Neurologic reinvestigation (day 34) revealed bilateral ptosis, weak bulbar elevation and abduction to the left, weak head anteflexion, diffuse tetraparesis with proximal predominance, diffuse wasting with distal accentuation, and generally reduced deep tendon reflexes. The serum creatine-kinase value was normal. Antinuclear antibodies were increased to 1:160 (normal, <1:40). Nerve conduction studies were indicative of an axonal polyneuropathy. Electromyography (anterior tibial) showed fibrillations, fasciculations and a single pseudomyotonic discharge at 6 of 20 sites, normal mean duration of the motor-unit action potentials, and reduced low-amplitude interference pattern. Visual evoked potentials showed markedly increased P100-latencies bilaterally. Muscle biopsy from the right deltoid muscle (day 36) showed angulated fibers, increased number of central nuclei, type I fiber predominance, and type II fiber atrophy. (5)

Since thyroid function had further deteriorated by day 29 (Table), leyothyroxine dosage was increased to 150 [micro]g/day. Despite this regimen, results of thyroid function tests were increasingly abnormal (Table). The levothyroxine dose was increased from 150 to 200 [micro]g on alternate days, but hypothyroidism persisted (Table). Impaired transformation of thyroxine to triiodothyronine was suspected, and liothyronine was added (day 50). With this regimen, respiratory function gradually improved until the patient no longer needed ventilatory support and could walk unaided. On the 64th hospital day, antibodies against thyroid peroxidase were increased to 182 U/mL (normal, 0 to 60 U/mL). Cholesterol and triglyceride levels were normal throughout hospitalization. Bone marrow aspiration was repeatedly refused by the patient.

DISCUSSION

Symptoms and signs occurring until thyroidectomy were attributed to hyperthyroidism after all other possible causes had been excluded. Worsening of these symptoms and the development of impaired visual acuity, dry skin, increasing fatigability, general weakness, wasting, and weight loss were attributed to hypothyroidism or malnutrition due to dysphagia. (1,3) Whether bradycardia and arterial hypotension were also due to hypothyroidism remains questionable. On admission, the cause of these symptoms remained unclear because results of thyroid function tests were normal. Since respiratory failure has not previously been described as a manifestation of hypothyroidism, it was initially interpreted as being due to polyradiculitis, myasthenia, paraneoplastic syndrome, or primary myopathy until exclusion of these differential diagnoses. Hypothyroidism was considered responsible for the respiratory abnormalities because of the persistently abnormal thyroid function tests and the good response to liothyronine.

The absent response to levothyroxine was attributed to impaired transformation of thyroxine into the active metabolite triiodothyronine by the dejodase (highest concentrations in the thyroid gland, liver, and brain, which were all impaired in our patient), since prompt recovery of respiratory functions was not seen before liothyronine was added. Underdosing is rather unlikely, since repeated increase of levothyroxine to a maximal dosage of 200 [micro]g/day had no effect. Impaired intestinal resorption could have been responsible, though administration of the drug in the fasting state was ineffective. Hypoproteinemia was excluded, because total protein was initially only slightly decreased and free [T.sub.3] values were normal. Indicator for an immunologic mechanism could be the increased titers of antinuclear and antithyroglobulin antibodies.

Whether weakness of the respiratory muscles was due to hypothyroid polyneuropathy or myopathy remains unclear. Arguments for polyneuropathy are the abnormal nerve conduction studies and the electromyography.(1,3-5) Possible causes of polyneuropathy other than hypothyroidism were excluded by application of an established screening program.(6) Arguments for myopathy are the low-amplitude interference pattern and the mild myopathic features on muscle biopsy.(7-9) However, duration, amplitude, and configuration of the motor-unit action potentials were almost normal, while the low-amplitude interference pattern was interpreted as being due to the axonal loss rather than myopathy. Possibly, the myopathic alterations seen on muscle biopsy were too subtle to induce remodeling of the motor-unit architecture that would affect the motor-unit action potential shape.

Whether the patient's anemia, thrombocytopenia, and monocytosis were due to a bone marrow abnormality or were causally related to hypothyroidism remains speculative. Indications for a possible relationship between thyroid dysfunction and thrombocytopenia are reports about the association of autoimmune thrombocytopenia and thyroid autoimmune disease.(10) Whether the repeatedly slightly increased serum [gamma]-globulins were attributable to a bone marrow process or were just an effect of the thyroid dysfunction also remains speculative. Hyponatremia has been reported to be associated with hypothyroidism, without an understanding of the underlying pathomechanism.(7) In our case, hypoproteinemia was attributed to malnutrition because of the longstanding dysphagia. Signs of demyelination on visual evoked potentials were attributed to the abnormalities shown on MRI rather than hypothyroidism.(3) Increased fatigability may have been due to hypothyroidism or the accompanying reactive depression. Serotonin reuptake i nhibitors were only poorly effective.

In conclusion, this case suggests that when total thyroidectomy leads to severe hypothyroidism, including respiratory failure despite replacement therapy with levothyroxin, liothyronine should be added.

TABLE

Patient's Blood Chemistry Values

                                                             Before
                                                           Admission

Parameter         Reference Range                        66 days

[T.sub.3]         0.6-1.9 x [10.sup.-9] g/[10.sup.-3] L   1.34
Free [T.sub.3]    2.0-4.25 pg/mL                          ND
Free [T.sub.4]    0.6-1.8 x [10.sup.-10]g/L               11.7 *
TSH               0.1-4.0 x [10.sup.-6] IU/[10.sub.-3[L   0.03 *
RBCs              4.0-5.2/pL                              ND
Platelets         150,000-450,000/[mm.sup.3]              57 *
Monocytes         2%-10%                                  20 *
Total protein     6.0-8.0 g/dL                            ND
[gamma]-globulin  10%-19%                                 24.1 *
Sodium            135-150 mEq/L                           137

                    Before                  Hospital Day
                  Admission

Parameter         42 days    1         8         18        20

[T.sub.3]          0.43 *   0.62      ND        ND        0.27 *
Free [T.sub.3]     ND       ND        ND        ND        ND
Free [T.sub.4]     0.65     1.61      ND        ND        0.93
TSH                10.84 *  1.31      ND        ND        8.06 *
RBCs               ND       ND        ND        3.83 *    3.81 *
Platelets          ND       ND        59 *      70 *      43 *
Monocytes          ND       ND        ND        ND        18.2 *
Total protein      ND       7.0       ND        ND        5.4
[gamma]-globulin   ND       ND        ND        ND        24.3 *
Sodium             ND       137       133 *     131 *     129 *

                                     Hospital Day

Parameter          25        29        39        48        50

[T.sub.3]         0.21 *    0.21 *    0.27 *    0.22 *    0.28 *
Free [T.sub.3]    ND        ND        ND        ND        1.61 *
Free [T.sub.4]    0.69      0.66      0.62      0.94      1.01
TSH               1.31 *    14.18 *   16.85 *   15.95 *   18.31 *
RBCs              4.12      3.58 *    2.29 *    3.26 *    3.99 *
Platelets         64 *      37 *      38 *      43 *      49 *
Monocytes         22 *      28.5 *    41 *      ND        ND
Total protein     ND        5.4       4.9       5.2       ND
[gamma]-globulin  ND        ND        20.6 *    ND        ND
Sodium            ND        132 *     129 *     ND        128

                                     Hospital Day

Parameter          53        60        64        68        76

[T.sub.3]         0.28 *    0.31 *    0.35 *    1.5       0.44 *
Free [T.sub.3]    2.91      ND        2.65      ND        2.18
Free [T.sub.4]    1.01      0.92      1.34      ND        1.05
TSH               8.13 *    13.7 *    3.0       0.73      1.96
RBCs              3.90 *    3.80 *    3.96 *    ND        3.53 *
Platelets         51 *      55 *      53 *      ND        90 *
Monocytes         ND        ND        ND        ND        ND
Total protein     ND        ND        5.6       ND        ND
[gamma]-globulin  ND        ND        ND        ND        ND
Sodium            125 *     136       140       134 *     130

                      Hospital Day

Parameter          77        84

[T.sub.3]         0.57 *    0.69
Free [T.sub.3]    ND        2.11
Free [T.sub.4]    1.11      1.44
TSH               2.84      0.37
RBCs              3.03 *    3.11 *
Platelets         93 *      56 *
Monocytes         ND        ND
Total protein     ND        ND
[gamma]-globulin  ND        ND
Sodium            134       136

[T.sub.3] = Triiodothyronine, [T.sub.4] = thyroxine, TSH = thyrotropin
(thyroid-stimulating hormone), RBC = red blood cells, ND = not done.

* Abnormal.

References

(1.) Duyff RF, Van den Bosch J, Laman DM, et al: Neuromuscular findings in thyroid dysfunction: a prospective clinical and electrodiagnostic study. J Neurol Neurosurg Psychiatry 2000; 68:750-755

(2.) Finsterer J, Stollberger C, Grossegger C, et al: Hypothyroid myopathy with unusually high serum creatine kinase values. Horm Res 1999; 52:205-208

(3.) Khedr EM, El Toony LF, Tarkhan MN, et al: Peripheral and central nervous system alterations in hypothyroidism: electrophysiological findings. Neuropsychobiology 2000; 41:88-94

(4.) Misiunas A, Niepomniszcze H, Ravera B, et al: Peripheral neuropathy in subclinical hypothyroidism. Thyroid 1995; 5:283-286

(5.) Torres CF, Moxley RT: Hypothyroid neuropathy and myopathy: clinical and electrodiagnostic longitudinal findings. J Neurol 1990; 237:271-274

(6.) Lubec D, Mullbacher W, Finsterer J, et al: Diagnostic work-up in peripheral neuropathy: an analysis of 171 cases. Postgrad Med J 1999; 75:723-727

(7.) Bhansali A, Chandran V, Ramesh J, et al: Acute myoedema: an unusual presenting manifestation of hypothyroid myopathy. Postgrad Med J 2000; 76:99-100

(8.) Lochmuller H, Reimers CD, Fischer P, et al: Exercise-induced myalgia in hypothyroidism. Clin Invest 1993; 71:999-1001

(9.) Modi G: Cores in hypothyroid myopathy: a clinical, histo-logical and immunofluorescence study. J Neurol Sci 2000; 175:28-32

(10.) Cordiano I, Betterle C, Spadaccino CA, et al: Autoimmune thrombocytopenia (AITP) and thyroid autoimmune disease (TAD): overlapping syndromes? Clin Exp Immunol 1998; 113:373-378

RELATED ARTICLE: KEY POINTS

* Hypothyroidism may lead to respiratory failure.

* Levothyroxine may be ineffective in hypothyroidism.

* Liothyronine may be helpful in hypothyroidism, if conversion of thyroxine to triiodothyronine is defective.

From the Neurologisches Krankenanstalt Rosenhugel, Vienna, Austria.

Reprint requests o Josef Finsterer, MD, PhD, Schindlergasse 9/10, Postfach 348, 1180 Vienna, Austria.