Clin J Gastroenterol (2009) 2:315–319 DOI 10.1007/s12328-009-0094-8
CASE REPORT
A case of severe cholestatic jaundice with hyperthyroidism successfully treated with methimazole Hitoshi Ichikawa Æ Hirotoshi Ebinuma Æ Shinichirou Tada Æ Keisuke Ojiro Æ Yoshiyuki Yamagishi Æ Nobuhiro Tsukada Æ Emi Hongou Æ Osamu Funae Æ Rie Irie Æ Hidetsugu Saito Æ Toshifumi Hibi
Received: 2 October 2008 / Accepted: 22 May 2009 / Published online: 17 June 2009 Ó Springer 2009
Abstract Liver dysfunction is a common complication observed in patients with hyperthyroidism, however the dysfunction is always mild and obvious jaundice is rarely observed. We present the case of a 43-year-old man who suffered from hyperthyroidism complicated by severe jaundice. The jaundice likely occurred as a secondary consequence of cholestasis due to hyperthyroidism, since other causes such as drug-induced or autoimmune liver dysfunction were ruled out. Treatment with methimazole improved severe cholestatic jaundice in parallel with normalization of thyroid function. The mechanism of cholestasis as a secondary complication of hyperthyroidism has not been uncovered and there is no specific biochemical marker for cholestasis due to this hormonal disease at present. This case serves as a reminder that severe jaundice can be a manifestation of simple hyperthyroidism, and that administration of antithyroid drugs is an effective treatment for severe cholestatic jaundice in such cases. Keywords
Hyperthyroidism Jaundice Cholestatis
H. Ichikawa H. Ebinuma S. Tada K. Ojiro Y. Yamagishi H. Saito (&) T. Hibi Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan e-mail: [email protected] R. Irie Division of Diagnostic Pathology, School of Medicine, Keio University, Tokyo, Japan N. Tsukada E. Hongou O. Funae Department of Internal Medicine, Saiseikai Central Hospital, Tokyo, Japan
Abbreviations CHD Congestive heart disease PBC Primary biliary cirrhosis AIH Autoimmune hepatitis DILI Drug-induced liver injury TB Total bilirubin AST Aspartate aminotransferase ALT Alanine aminotransferase ALP Alkaline phosphatase cGTP Gamma-glutamyltranspeptidase TSH Thyroid-stimulating hormone MMI Methimazole PTU Propylthiouracil
Introduction Abnormalities in liver biochemical tests are often observed in patients with hyperthyroidism even in the absence of hyperthyroid storm, but the disease severity is always very mild. Although increased bilirubin levels or jaundice are occasionally observed, such cases are mostly associated with complications due to congestive heart disease (CHD) or other liver diseases such as primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH). At present, medical treatment with antithyroid drugs is recommended and widely used for hyperthyroidism, but treatment of hyperthyroidism patients with severe liver dysfunction is often limited by the increased possibility of drug side effects due to liver dysfunction. In such cases, it can be difficult to differentially diagnose whether the liver function abnormality results from hyperthyroidism itself or from druginduced liver injury (DILI). We report here a case of hyperthyroidism with severe cholestatic jaundice probably not due to DILI.
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Case report A 43-year-old man transferred to our hospital for the treatment of severe cholestasis with hyperthyroidism. He experienced dark urine and pruritus in late April 2006 and his body weight declined by 7 kg during the previous 1 month before visiting the regional hospital. In May 2006, the patient’s family noticed that he was jaundiced; he consulted a physician and was then hospitalized in the regional hospital. He revealed that he had hypertension but had received no medication for the condition. He had continued smoking 20 cigarettes a day for 20 years and consumed 1500 ml of beer twice a week, although his alcohol consumption had declined in the prior 3 weeks. He had no history of hepatitis, blood transfusion, intravenous drug abuse, skin tattoos, or prior liver dysfunction. When he was hospitalized in the regional hospital, remarkable jaundice and slight palpable hepatomegaly were evident, but he did not have struma or tremor. The laboratory data showed 17.1 mg/dl (normal range: 0.2– 1.0 mg/dl) serum total bilirubin (TB), 38 IU/l (8–38 IU/l) aspartate aminotransferase (AST), 64 IU/l (4–44 IU/l) alanine aminotransferase (ALT), 488 IU/l (104–338 IU/l) alkaline phosphatase (ALP), and 42 IU/l (16–73 IU/l) gamma-glutamyltranspeptidase (cGTP). Blood cell count and coagulation test results were normal. The patient was negative for viral markers, including IgM hepatitis A antibody, hepatitis B surface antigen, hepatitis C antibody, IgM cytomegalovirus antibody, and IgM Epstein-Barr virus antibody and for autoantibodies, including antinuclear antibody and anti-mitochondrial M2 antibody. Abdominal ultrasonography and computed tomography indicated no abnormal findings. Chest X-ray and electrocardiogram results were also within normal limits. His free T3 level was 5.4 pg/dl (2.2–4.1 pg/dl), free T4 level was 8.4 ng/dl (0.8–1.7 pg/dl) and thyroid-stimulating hormone (TSH) level was less than 0.01 lIU/ml (0.35–4.00 pg/dl). His TSH receptor antibody level was 58.4% (0–15%), thyroid peroxidase antibody was 25 U/ml (\0.3 U/ml), and TSH stimulating antibody was 250% (\179%). Ultrasonography of his thyroid indicated that its size was at the upper limit of the normal range and the echo level was slightly low and irregular but there were no focal lesions. He was diagnosed with Graves’ disease based on his clinical symptoms and the existence of the aforementioned autoantibodies. Pathological findings from a liver needle biopsy showed severe cholestasis in hepatocytes, bile capillaries and hepatocyte necrosis; moderate neutrophil and lymphocyte infiltration were found in zone 3, while only mild cell infiltration was observed in zone 1 (Fig. 2a). No apparent fibrosis was noted. Because the patient had not received medication, and other causes of liver dysfunction had been excluded, he
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Clin J Gastroenterol (2009) 2:315–319 Table 1 Laboratory data at admission (23 June 2006) TP (6.7–8.2 g/dl)
7.1
WBC (3500–8500/ll)
6400
ALB (3.9–5.2 g/dl)
3.2
RBC (430–570 9 104/ll)
334 9 104
TB (0.4–1.3 mg/dl)
17.6
Hgb (13.5–17.0 g/dl)
10.2
DB (\0.2 mg/dl)
12.8
Hct (40.0–50.0%)
30.4
LDH (120–240 IU/l)
160
PLT (150–350 9 103/ll)
374 9 103
AST (10–35 IU/l)
50
APTT (23.0–36.0 s)
27.0
ALT (5–40 IU/l)
57
PT-INR (0.80–1.20)
0.99
ALP (100–320 IU/l)
713
Free T3 (2.0–4.5 pg/dl)
6.9
GGTP (10–90 IU/l)
70
Free T4 (0.7–1.8 pg/dl)
3.6
TC (135–240 IU/l)
152
TSH (0.30–4.50 lIU/ml)
\0.01
TRAb (\1.0 IU/l)
7.4
WBC white blood cells, RBC red blood cells, Hgb hemoglobin, Hct hematocrit, PLT platelet, APTT activated partial thromboplastin time, PT-INR prothrombin time-international normalized ratio, TP total protein, ALB albumin, TB total bilirubin, DB direct bilirubin, TC total cholesterol, TRAb TSH receptor antibody
was diagnosed with cholestasis due to Graves’ disease. His general fatigue and pruritus gradually worsened during his medical check-up and his TB level increased to 39.4 mg/dl (direct bilirubin 21.2 mg/dl). He was subsequently treated with 600 mg/day of ursodeoxycholic acid (UDCA) and 50 mg/day of potassium iodide. Afterwards, his TB levels decreased to 24 mg/dl but cholestasis and hyperthyroidism were not sufficiently improved; he was then transferred to our hospital in June. The patient’s laboratory data at the time of admission to our hospital are summarized in Table 1. In the event that the patient’s cholestasis was caused by hyperthyroidism, we deemed it necessary to normalize thyroid function. We therefore treated the patient with 15 mg/day of methimazole
Fig. 1 Serial change in laboratory tests. TB is indicated by a black circle and solid line, ALT by a gray square and dotted line, ALP by a black square and dotted line, and cGTP by a gray circle and solid line. These laboratory data improved after treatment with MMI and finally normalized
Clin J Gastroenterol (2009) 2:315–319
317
Fig. 2 Pathological findings before and after treatment. Pathological findings before treatment indicated severe cholestasis in hepatocytes and bile capillaries and the necrosis of hepatocytes with neutrophil and lymphocyte infiltration in the central vein area, but only mild neutrophil and lymphocyte infiltration in the portal area (left), Pathological findings after treatment indicated improvement of severe cholestasis (right)
(MMI) starting on 22 June. After the administration of MMI, the free f-T4 level fell to within normal range in about 1 month and the TSH level normalized within about 3 months. In addition, the levels of TB and other liver biochemical parameters also fell gradually to within normal range in about 1 month. The pathological findings after the administration of MMI (in July) showed remarkable improvement of cholestasis and slight improvement of lymphocyte infiltration and necrosis of hepatocytes in the central area (Fig. 2b). To date, the patient has continued to take MMI and his thyroid function, as well as his liver function, have been maintained within normal range (Fig. 1).
Discussion Various abnormalities of liver biochemical parameters have been reported in patients with hyperthyroidism since the initial report of this disease entity by Harberson et al. [1] in 1874. Mild and nonspecific increases in serum transaminase and ALP are commonly observed with a frequency varying 15 to 76% [2]. Increased TB levels are also observed in 5 to 65% of patients with hyperthyroidism [2]. However, most cases of hyperbilirubinemia in patients with hyperthyroidism are complicated by CHF [3] or other liver diseases such as PBC [4] and AIH [5]. Jaundice was described as an apparent feature of thyrotoxicosis back in the era when antithyroid therapy was less effective than the therapies that are
currently available [6]. Indeed, Thompson et al. [7] reported that hyperbilirubinemia was found in 31% of 65 patients with hyperthyroidism and the maximum value was 3.5 mg/ dl. Huang et al. [2] also reported finding this abnormality in 5.3% of 95 patients with hyperthyroidism and the maximum value was 2.6 mg/dl. In our case, the maximum TB level (39.4 mg/dl) was excessively high, which led us to suspect that the cholestasis might not be caused by hyperthyroidism alone. However, the scientific literature describes some cases of severe cholestasis linked with hyperthyroidism. Yao et al. [9] reported a case of marked cholestatic jaundice (maximum TB level of 286 lM, which corresponds to 16.7 mg/dl) as a complication of hyperthyroidism in the absence of CHF. Several other case reports describing severe cholestasis (TB [ 10 mg/dl) were subsequently reported [10–12]. In one of those cases, the maximal TB level was 42 mg/dl, which is as high as in our case [11]. Interestingly, cholestasis did not parallel the degree of hyperthyroidism (levels of free T3, free T4, and TSH), but it did improve in parallel with improvement of hyperthyroidism during therapy [8]. In this case, the severe cholestasis improved gradually and reached normal range within about 1 month after the first administration of MMI, as did the patient’s thyroid hormone levels. This clinical course suggests that the severe cholestasis in this case was due to hyperthyroidism. However, the patient’s TB level began to decrease after UDCA administration and we therefore concluded that UDCA was partially effective in improving his cholestasis, although his ALP and cGTP levels were still
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increased after UDCA administration in spite of the improvement of his TB level. There are no reports that we are aware of in which UDCA has been shown to be effective for treating cholestasis due to hyperthyroidism, so we reasoned that additional treatment for Graves’ disease was necessary. The mechanism of liver injury in hyperthyroidism is not well understood, but it has been suggested that the damage to hepatocytes is caused by relative centrilobular hypoxia due to increased hepatocyte demand for oxygen without a concomitant increase hepatic blood flow [13]. The pathological findings of the liver in patients with hyperthyroidism described in previous studies ranged from steatosis to hepatitis or cirrhosis, but most of these reports were autopsy cases and therefore other causes besides hyperthyroidism could not be excluded [14–16]. Movitt et al. [17] reported nuclear polymorphism with hyperchromatism, vacuolated nuclei, eosinophilic infiltration, and steatosis in 13 cases of liver needle biopsies from patients with hyperthyroidism. Sola et al. [18] observed mild to moderate intrahepatocytic cholestasis, lobular inflammatory infiltrate with some eosinophils, and Kupffer cell hyperplasia in 5 cases of hyperthyroidism. Fong et al. [19] noted non-specific changes such as Kupffer cell hyperplasia, glycogen nuclei, hydropic changes, and random mild focal necrosis in patients with hyperthyroidism. These reports indicate that there is no specific hallmark pathological finding in the livers of patients with hyperthyroidism. Moreover, the degree of liver dysfunction, such as the levels of TB or ALT, does not correlate with pathological findings [20]. The pathological findings in our case were severe bile stasis in hepatocytes and bile capillaries and necrosis of hepatocytes with neutrophil and lymphocyte infiltration mainly in the central areas, and this finding was non-specific (Fig. 2a). In addition, these pathologic findings were remarkably improved in the second biopsy (Fig. 2b) when hyperthyroidism was successfully treated, and thus, these findings were compatible with previous reports as described above. In general, the administration of anti-thyroid drugs such as MMI or propylthiouracil (PTU) has been widely used for the initial treatment of hyperthyroidism. These anti-thyroid drugs sometimes show adverse effects such as agranulocytosis, skin eruption, liver dysfunction, systemic lupus erythematosus-like syndrome, and arthritic pain. Liver dysfunction is especially common with PTU which sometimes can be serious [22]. Liau et al. [21] reported increased ALT levels after administration of PTU in 28% of patients with hyperthyroidism who had normal liver function prior to treatment. In contrast, liver dysfunction induced by MMI seems to be rare; there are fewer than 30 such case reports, and in all cases the liver dysfunction appeared anywhere from 3 days to 5 months after
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administration of MMI [23]. In our case, the doctor in the former hospital prescribed potassium iodide for the treatment of hyperthyroidism because he was anxious about the possibility of further liver injury by MMI, which has been reported to induce cholestasis [24]. Worsening of cholestasis in a patient with hyperthyroidism by administration of PTU has also been reported [12]. In addition to irradiation therapy, carbimazole has been reported to improve cholestatic jaundice as well as hyperthyroidism [10, 25]. MMI-induced liver injury is rare and it has been reported that although the pattern of liver injury varies, the most common pathological finding is intrahepatic cholestasis [25]. Although these reports made us hesitant to administer MMI for Graves’ disease in our patient with cholestasis, we deemed that the patient’s severe cholestasis resulted from the hyperthyroidism and that it would therefore be relatively safe to treat this patient with MMI. Severe cholestatic jaundice due to hyperthyroidism is rare and there are at present no reliable biochemical markers for the diagnosis of cholestasis due to hyperthyroidism. We should keep in mind that successful treatment of hyperthyroidism will improve liver dysfunction and even cholestasis, but careful selection of drugs used to treat hyperthyroidism is necessary for successful treatment.
References 1. Habershon. Exophthalmic goiter; heart disease; jaundice; death. Lancet 1874;103:510. 2. Huang M-J, Liaw Y-F. Clinical associations between thyroid and liver diseases. J Gastroenterol Hepatol. 1995;10:344–50. 3. Lee TM, Kuo SH, Lee YT. Case report: reversible systolic heart failure and deep jaundice in hyperthyroidism. Am J Med Sci. 1996;312:246–8. 4. Thompson NP, Leader S, Jamieson CP, Burnham WR, Burroughs AK. Reversible jaundice in primary biliary cirrhosis due to hyperthyroidism. Gastroenterology. 1994;106:1342–3. 5. Thompson WG, Hart IR. Chronic active hepatitis and Graves’ disease. Dig Dis Sci. 1973;18:111–8. 6. Schiff L, Schiff ER. Schiff’s diseases of the liver. 7th ed. Philadelphia: JB Lippincott; 1993. p. 1389. 7. Thompson P, Boehm T, Strum D, Wartofsky L. Abnormalities of liver function tests in thyrotoxicosis. Mil Med. 1978;143:548–51. 8. Huang M-J, Li KL, Wei JS, Wu SS, Fan KD, Liaw YF. Sequential liver and bone biochemical changes in hyperthyroidism: prospective controlled follow-up study. Am J Gastroenterol. 1994;89:1071–6. 9. Yao JD, Gross JB Jr, Ludwig J, Purnell DC. Cholestatic jaundice in hyperthyroidism. Am J Med. 1989;86:619–20. 10. Barnes SC, Wicking JM, Johnston JD. Grave’s disease presenting with cholestatic jaundice. Ann Clin Biochem. 1999;36:677–9. 11. Hull K, Horenstein R, Naglieri R, Munir K, Ghany M, Celi FS. Two cases of thyroid storm-associated cholestatic jaundice. Endocr Pract. 2007;13:476–80. 12. Soylu A, Taskale MG, Ciltas A, Kalayci M, Kumbasar AB. Intrahepatic cholestasis in subclinical and overt hyperthyroidism: two case reports. J Med Case Rep. 2008;2:116.
Clin J Gastroenterol (2009) 2:315–319 13. Myers JD, Brannon ES, Holland BC. A correlative study of cardiac output and the hepatic circulation in hyperthyroidism. J Clin Invest. 1950;29:1069–77. 14. Beaver DC, Pemberton J. Pathologic anatomy of the liver in exophthalmic goiter. Ann Intern Med. 1933;7:687–94. 15. Weller CV. Hepatic pathology in exophthalmic goiter. Ann Intern Med. 1933;7:543–50. 16. Shaffer JM. Disease of the liver in hyperthyroidism. Arch Pathol. 1940;29:20–30. 17. Movitt ER, Gerstl B, Davis AE. Needle liver biopsy in thyrotoxicosis. Arch Intern Med. 1953;91:729–30. 18. Sola J, Pardo-Minda´n FJ, Zozaya J, Quiroga J, Sangro B, Prieto J. Liver changes in patients with hyperthyroidism. Liver. 1991;11: 193–7. 19. Fong TL, McHutchison JG, Reynolds TB. Hyperthyroidism and hepatic dysfunction. A case series analysis. J Clin Gastroenterol. 1992;14:240–4.
319 20. Dooner HP, Parada J, Aliage C, Hoyl C. The liver in thyrotoxicosis. Arch Intern Med. 1967;120:25–32. 21. Liau YF, Huang MJ, Fan KD, Li KL, Wu SS, Chen TJ. Hepatic injury during propylthiouracil therapy in patients with hyperthyroidism. A cohort study. Ann Intern Med. 1993;118:424–8. 22. Jonas MM, Eidson MS. Propylthiouracil hepatotoxicity: two pediatric cases and review of the literature. J Pediatr Gastroenterol Nutr. 1988;7:776–9. 23. Mikhail NE. Methimazole-induced cholestatic jaundice. South Med J. 2004;97:178–82. 24. Majeed M, Babu A. Cholestasis secondary to hyperthyroidism made worse by methimazole. Am J Med Sci. 2006;332:51–3. 25. Viallard JF, Tabarin A, Neau D, Longy-Boursier M. Hyperthyroidism with severe intrahepatic cholestasis. Dig Dis Sci. 1999;44: 2001–2.
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CASE REPORT
A case of severe cholestatic jaundice with hyperthyroidism successfully treated with methimazole Hitoshi Ichikawa Æ Hirotoshi Ebinuma Æ Shinichirou Tada Æ Keisuke Ojiro Æ Yoshiyuki Yamagishi Æ Nobuhiro Tsukada Æ Emi Hongou Æ Osamu Funae Æ Rie Irie Æ Hidetsugu Saito Æ Toshifumi Hibi
Received: 2 October 2008 / Accepted: 22 May 2009 / Published online: 17 June 2009 Ó Springer 2009
Abstract Liver dysfunction is a common complication observed in patients with hyperthyroidism, however the dysfunction is always mild and obvious jaundice is rarely observed. We present the case of a 43-year-old man who suffered from hyperthyroidism complicated by severe jaundice. The jaundice likely occurred as a secondary consequence of cholestasis due to hyperthyroidism, since other causes such as drug-induced or autoimmune liver dysfunction were ruled out. Treatment with methimazole improved severe cholestatic jaundice in parallel with normalization of thyroid function. The mechanism of cholestasis as a secondary complication of hyperthyroidism has not been uncovered and there is no specific biochemical marker for cholestasis due to this hormonal disease at present. This case serves as a reminder that severe jaundice can be a manifestation of simple hyperthyroidism, and that administration of antithyroid drugs is an effective treatment for severe cholestatic jaundice in such cases. Keywords
Hyperthyroidism Jaundice Cholestatis
H. Ichikawa H. Ebinuma S. Tada K. Ojiro Y. Yamagishi H. Saito (&) T. Hibi Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan e-mail: [email protected] R. Irie Division of Diagnostic Pathology, School of Medicine, Keio University, Tokyo, Japan N. Tsukada E. Hongou O. Funae Department of Internal Medicine, Saiseikai Central Hospital, Tokyo, Japan
Abbreviations CHD Congestive heart disease PBC Primary biliary cirrhosis AIH Autoimmune hepatitis DILI Drug-induced liver injury TB Total bilirubin AST Aspartate aminotransferase ALT Alanine aminotransferase ALP Alkaline phosphatase cGTP Gamma-glutamyltranspeptidase TSH Thyroid-stimulating hormone MMI Methimazole PTU Propylthiouracil
Introduction Abnormalities in liver biochemical tests are often observed in patients with hyperthyroidism even in the absence of hyperthyroid storm, but the disease severity is always very mild. Although increased bilirubin levels or jaundice are occasionally observed, such cases are mostly associated with complications due to congestive heart disease (CHD) or other liver diseases such as primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH). At present, medical treatment with antithyroid drugs is recommended and widely used for hyperthyroidism, but treatment of hyperthyroidism patients with severe liver dysfunction is often limited by the increased possibility of drug side effects due to liver dysfunction. In such cases, it can be difficult to differentially diagnose whether the liver function abnormality results from hyperthyroidism itself or from druginduced liver injury (DILI). We report here a case of hyperthyroidism with severe cholestatic jaundice probably not due to DILI.
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Case report A 43-year-old man transferred to our hospital for the treatment of severe cholestasis with hyperthyroidism. He experienced dark urine and pruritus in late April 2006 and his body weight declined by 7 kg during the previous 1 month before visiting the regional hospital. In May 2006, the patient’s family noticed that he was jaundiced; he consulted a physician and was then hospitalized in the regional hospital. He revealed that he had hypertension but had received no medication for the condition. He had continued smoking 20 cigarettes a day for 20 years and consumed 1500 ml of beer twice a week, although his alcohol consumption had declined in the prior 3 weeks. He had no history of hepatitis, blood transfusion, intravenous drug abuse, skin tattoos, or prior liver dysfunction. When he was hospitalized in the regional hospital, remarkable jaundice and slight palpable hepatomegaly were evident, but he did not have struma or tremor. The laboratory data showed 17.1 mg/dl (normal range: 0.2– 1.0 mg/dl) serum total bilirubin (TB), 38 IU/l (8–38 IU/l) aspartate aminotransferase (AST), 64 IU/l (4–44 IU/l) alanine aminotransferase (ALT), 488 IU/l (104–338 IU/l) alkaline phosphatase (ALP), and 42 IU/l (16–73 IU/l) gamma-glutamyltranspeptidase (cGTP). Blood cell count and coagulation test results were normal. The patient was negative for viral markers, including IgM hepatitis A antibody, hepatitis B surface antigen, hepatitis C antibody, IgM cytomegalovirus antibody, and IgM Epstein-Barr virus antibody and for autoantibodies, including antinuclear antibody and anti-mitochondrial M2 antibody. Abdominal ultrasonography and computed tomography indicated no abnormal findings. Chest X-ray and electrocardiogram results were also within normal limits. His free T3 level was 5.4 pg/dl (2.2–4.1 pg/dl), free T4 level was 8.4 ng/dl (0.8–1.7 pg/dl) and thyroid-stimulating hormone (TSH) level was less than 0.01 lIU/ml (0.35–4.00 pg/dl). His TSH receptor antibody level was 58.4% (0–15%), thyroid peroxidase antibody was 25 U/ml (\0.3 U/ml), and TSH stimulating antibody was 250% (\179%). Ultrasonography of his thyroid indicated that its size was at the upper limit of the normal range and the echo level was slightly low and irregular but there were no focal lesions. He was diagnosed with Graves’ disease based on his clinical symptoms and the existence of the aforementioned autoantibodies. Pathological findings from a liver needle biopsy showed severe cholestasis in hepatocytes, bile capillaries and hepatocyte necrosis; moderate neutrophil and lymphocyte infiltration were found in zone 3, while only mild cell infiltration was observed in zone 1 (Fig. 2a). No apparent fibrosis was noted. Because the patient had not received medication, and other causes of liver dysfunction had been excluded, he
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Clin J Gastroenterol (2009) 2:315–319 Table 1 Laboratory data at admission (23 June 2006) TP (6.7–8.2 g/dl)
7.1
WBC (3500–8500/ll)
6400
ALB (3.9–5.2 g/dl)
3.2
RBC (430–570 9 104/ll)
334 9 104
TB (0.4–1.3 mg/dl)
17.6
Hgb (13.5–17.0 g/dl)
10.2
DB (\0.2 mg/dl)
12.8
Hct (40.0–50.0%)
30.4
LDH (120–240 IU/l)
160
PLT (150–350 9 103/ll)
374 9 103
AST (10–35 IU/l)
50
APTT (23.0–36.0 s)
27.0
ALT (5–40 IU/l)
57
PT-INR (0.80–1.20)
0.99
ALP (100–320 IU/l)
713
Free T3 (2.0–4.5 pg/dl)
6.9
GGTP (10–90 IU/l)
70
Free T4 (0.7–1.8 pg/dl)
3.6
TC (135–240 IU/l)
152
TSH (0.30–4.50 lIU/ml)
\0.01
TRAb (\1.0 IU/l)
7.4
WBC white blood cells, RBC red blood cells, Hgb hemoglobin, Hct hematocrit, PLT platelet, APTT activated partial thromboplastin time, PT-INR prothrombin time-international normalized ratio, TP total protein, ALB albumin, TB total bilirubin, DB direct bilirubin, TC total cholesterol, TRAb TSH receptor antibody
was diagnosed with cholestasis due to Graves’ disease. His general fatigue and pruritus gradually worsened during his medical check-up and his TB level increased to 39.4 mg/dl (direct bilirubin 21.2 mg/dl). He was subsequently treated with 600 mg/day of ursodeoxycholic acid (UDCA) and 50 mg/day of potassium iodide. Afterwards, his TB levels decreased to 24 mg/dl but cholestasis and hyperthyroidism were not sufficiently improved; he was then transferred to our hospital in June. The patient’s laboratory data at the time of admission to our hospital are summarized in Table 1. In the event that the patient’s cholestasis was caused by hyperthyroidism, we deemed it necessary to normalize thyroid function. We therefore treated the patient with 15 mg/day of methimazole
Fig. 1 Serial change in laboratory tests. TB is indicated by a black circle and solid line, ALT by a gray square and dotted line, ALP by a black square and dotted line, and cGTP by a gray circle and solid line. These laboratory data improved after treatment with MMI and finally normalized
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317
Fig. 2 Pathological findings before and after treatment. Pathological findings before treatment indicated severe cholestasis in hepatocytes and bile capillaries and the necrosis of hepatocytes with neutrophil and lymphocyte infiltration in the central vein area, but only mild neutrophil and lymphocyte infiltration in the portal area (left), Pathological findings after treatment indicated improvement of severe cholestasis (right)
(MMI) starting on 22 June. After the administration of MMI, the free f-T4 level fell to within normal range in about 1 month and the TSH level normalized within about 3 months. In addition, the levels of TB and other liver biochemical parameters also fell gradually to within normal range in about 1 month. The pathological findings after the administration of MMI (in July) showed remarkable improvement of cholestasis and slight improvement of lymphocyte infiltration and necrosis of hepatocytes in the central area (Fig. 2b). To date, the patient has continued to take MMI and his thyroid function, as well as his liver function, have been maintained within normal range (Fig. 1).
Discussion Various abnormalities of liver biochemical parameters have been reported in patients with hyperthyroidism since the initial report of this disease entity by Harberson et al. [1] in 1874. Mild and nonspecific increases in serum transaminase and ALP are commonly observed with a frequency varying 15 to 76% [2]. Increased TB levels are also observed in 5 to 65% of patients with hyperthyroidism [2]. However, most cases of hyperbilirubinemia in patients with hyperthyroidism are complicated by CHF [3] or other liver diseases such as PBC [4] and AIH [5]. Jaundice was described as an apparent feature of thyrotoxicosis back in the era when antithyroid therapy was less effective than the therapies that are
currently available [6]. Indeed, Thompson et al. [7] reported that hyperbilirubinemia was found in 31% of 65 patients with hyperthyroidism and the maximum value was 3.5 mg/ dl. Huang et al. [2] also reported finding this abnormality in 5.3% of 95 patients with hyperthyroidism and the maximum value was 2.6 mg/dl. In our case, the maximum TB level (39.4 mg/dl) was excessively high, which led us to suspect that the cholestasis might not be caused by hyperthyroidism alone. However, the scientific literature describes some cases of severe cholestasis linked with hyperthyroidism. Yao et al. [9] reported a case of marked cholestatic jaundice (maximum TB level of 286 lM, which corresponds to 16.7 mg/dl) as a complication of hyperthyroidism in the absence of CHF. Several other case reports describing severe cholestasis (TB [ 10 mg/dl) were subsequently reported [10–12]. In one of those cases, the maximal TB level was 42 mg/dl, which is as high as in our case [11]. Interestingly, cholestasis did not parallel the degree of hyperthyroidism (levels of free T3, free T4, and TSH), but it did improve in parallel with improvement of hyperthyroidism during therapy [8]. In this case, the severe cholestasis improved gradually and reached normal range within about 1 month after the first administration of MMI, as did the patient’s thyroid hormone levels. This clinical course suggests that the severe cholestasis in this case was due to hyperthyroidism. However, the patient’s TB level began to decrease after UDCA administration and we therefore concluded that UDCA was partially effective in improving his cholestasis, although his ALP and cGTP levels were still
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increased after UDCA administration in spite of the improvement of his TB level. There are no reports that we are aware of in which UDCA has been shown to be effective for treating cholestasis due to hyperthyroidism, so we reasoned that additional treatment for Graves’ disease was necessary. The mechanism of liver injury in hyperthyroidism is not well understood, but it has been suggested that the damage to hepatocytes is caused by relative centrilobular hypoxia due to increased hepatocyte demand for oxygen without a concomitant increase hepatic blood flow [13]. The pathological findings of the liver in patients with hyperthyroidism described in previous studies ranged from steatosis to hepatitis or cirrhosis, but most of these reports were autopsy cases and therefore other causes besides hyperthyroidism could not be excluded [14–16]. Movitt et al. [17] reported nuclear polymorphism with hyperchromatism, vacuolated nuclei, eosinophilic infiltration, and steatosis in 13 cases of liver needle biopsies from patients with hyperthyroidism. Sola et al. [18] observed mild to moderate intrahepatocytic cholestasis, lobular inflammatory infiltrate with some eosinophils, and Kupffer cell hyperplasia in 5 cases of hyperthyroidism. Fong et al. [19] noted non-specific changes such as Kupffer cell hyperplasia, glycogen nuclei, hydropic changes, and random mild focal necrosis in patients with hyperthyroidism. These reports indicate that there is no specific hallmark pathological finding in the livers of patients with hyperthyroidism. Moreover, the degree of liver dysfunction, such as the levels of TB or ALT, does not correlate with pathological findings [20]. The pathological findings in our case were severe bile stasis in hepatocytes and bile capillaries and necrosis of hepatocytes with neutrophil and lymphocyte infiltration mainly in the central areas, and this finding was non-specific (Fig. 2a). In addition, these pathologic findings were remarkably improved in the second biopsy (Fig. 2b) when hyperthyroidism was successfully treated, and thus, these findings were compatible with previous reports as described above. In general, the administration of anti-thyroid drugs such as MMI or propylthiouracil (PTU) has been widely used for the initial treatment of hyperthyroidism. These anti-thyroid drugs sometimes show adverse effects such as agranulocytosis, skin eruption, liver dysfunction, systemic lupus erythematosus-like syndrome, and arthritic pain. Liver dysfunction is especially common with PTU which sometimes can be serious [22]. Liau et al. [21] reported increased ALT levels after administration of PTU in 28% of patients with hyperthyroidism who had normal liver function prior to treatment. In contrast, liver dysfunction induced by MMI seems to be rare; there are fewer than 30 such case reports, and in all cases the liver dysfunction appeared anywhere from 3 days to 5 months after
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administration of MMI [23]. In our case, the doctor in the former hospital prescribed potassium iodide for the treatment of hyperthyroidism because he was anxious about the possibility of further liver injury by MMI, which has been reported to induce cholestasis [24]. Worsening of cholestasis in a patient with hyperthyroidism by administration of PTU has also been reported [12]. In addition to irradiation therapy, carbimazole has been reported to improve cholestatic jaundice as well as hyperthyroidism [10, 25]. MMI-induced liver injury is rare and it has been reported that although the pattern of liver injury varies, the most common pathological finding is intrahepatic cholestasis [25]. Although these reports made us hesitant to administer MMI for Graves’ disease in our patient with cholestasis, we deemed that the patient’s severe cholestasis resulted from the hyperthyroidism and that it would therefore be relatively safe to treat this patient with MMI. Severe cholestatic jaundice due to hyperthyroidism is rare and there are at present no reliable biochemical markers for the diagnosis of cholestasis due to hyperthyroidism. We should keep in mind that successful treatment of hyperthyroidism will improve liver dysfunction and even cholestasis, but careful selection of drugs used to treat hyperthyroidism is necessary for successful treatment.
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