Hepatic dysfunction in a patient with thyrotoxicosis may result from hyperthyroidism per se, as a side effect of antithyroid drugs, and causes unrelated to hyperthyroidism which sometimes causes diagnostic and therapeutic difficulties. A young female patient was admitted to our hospital with symptoms of thyrotoxicosis, diffuse goiter and ophthalmopathy along with cholestatic pattern of jaundice, and proximal muscle weakness. She was treated with propylthiouracil with gradual recovery. She was continuing her antithyroid medication with regular follow-up. The patient was readmitted a few months later with worsening thyrotoxicosis, proximal muscle weakness, fever, and a hepatocellular pattern of jaundice with sepsis. Propylthiouracil was stopped and lithium along with steroid coverage was given to control her thyrotoxicosis which was later changed to methimazole. Broad spectrum antibiotic therapy was also started but without any response. During her hospital stay, the patient also developed a flaccid paraplegia resembling Guillain-Barre syndrome. IV steroid was started for the neuropathy but meanwhile the patient succumbed to her illness. So in centers where facility for radioiodine therapy is not readily available, some definite well-tested protocols should be formulated to address such common but complicated clinical situations.
Hepatic dysfunction in patients with thyrotoxicosis may be caused by hyperthyroidism per se, as a side effect of drugs used to treat hyperthyroidism and associated rare conditions like autoimmune hepatitis or causes unrelated to hyperthyroidism like viral hepatitis, alcohol abuse, sepsis, cholangitis, or certain medications. Uncomplicated hyperthyroidism causing severe hepatic dysfunction is, however, rare. It was first reported by Habershon in 1874 [
A 26-year-old female patient presented with symptoms of thyrotoxicosis in the form of palpitation, progressive weight loss in spite of increased appetite, hyperdefecation, and anxiety along with neck swelling and bulging of her eye balls for last 2 years. She also developed jaundice for last 2 months and proximal muscle weakness for last 15 days. Physical examination revealed a BMI of 15.79 kg/m2, resting tachycardia, a wide pulse pressure, and warm and moist extremities with diffuse thyromegaly and ophthalmopathy suggesting Grave’s disease. Other significant physical findings were icterus, mild hepatomegaly with normal jugular venous pressure, and a predominantly proximal muscle weakness with preservation of the deep tendon reflexes. Laboratory investigations revealed significant suppression of thyroid stimulating hormone (TSH) (0.056 IU/L) and high free serum T4 (3.45 ng/dL) and serum T3 (4.56 nmol/L). Liver function tests revealed total bilirubin levels of 15.8 mg/dL with a predominantly conjugated fraction (12.6 mg/dL), an abnormal alkaline phosphatase of 364 U/L, and an AST and ALT of 46 U/L and 43 U/L, respectively, suggestive of a cholestatic pattern. Coagulation studies were within normal limits. Screening for routine viral markers was all negative. She was also found to have hypokalemia which was thought to be due to an intracellular shift of potassium because of thyrotoxicosis as no other cause for hypokalemia was found. Similarly she was also evaluated for myopathy, but no obvious cause was found apart from thyrotoxicosis.
The baseline investigations of the patient are shown in Table
Baseline investigations of the patient.
TSH (mIU/L) |
|
Serum alkaline phosphatase (SAP) (U/L) (38–126) |
|
FT4 (ng/dL) (0.89–1.7) |
|
S. albumin (g/dL) | 3.3 |
T3 (nmol/L) (1.25–2.74) |
|
Prothrombin time (sec) | 14.2 |
Anti-TPO Ab (IU/dL) | 450 | Serum CPK | Normal |
Bilirubin (total) (mg/dL) |
|
USG abdomen | Hepatomegaly with periportal cuffing suggestive of acute hepatitis |
Conjugated (mg/dL) |
|
Viral markers (HVB, HCV, HAV, and HEV) | Negative |
Unconjugated (mg/dL) | 1.5 | Arterial blood gas analysis (ABG) | Normal |
AST (U/L) | 46 | 24-hour urinary potassium | Normal |
ALT (U/L) | 43 | S. Na+/K+ (mmol/L) | 134/2.7 |
Considering her cholestatic pattern of jaundice she was started on tab propylthiouracil (PTU) at a dose of 50 mg twice daily and nonselective
The follow-up investigations of the patient are shown in Table
Follow-up investigations of the patient.
At adm. | 1st wk | 2nd wk | 3rd wk | At disch. | 2nd month | 5th month | 6th month | |
---|---|---|---|---|---|---|---|---|
TSH (mIU/L) | 0.056 | 0.28 | — | 0.45 | 0.78 | |||
FT4 (ng/dL) (0.89–1.7) |
|
|
|
|
|
|||
T3 (nmol/L) | 4.56 | 3.34 | 3.3 | 2.67 | 2.01 | |||
S. bilirubin (Total) (mg/dL) | 15.8 | 10.5 | 8.4 | 5.5 | 4.5 | 4.14 | 3.5 | 3.12 |
Conjugated (mg/dL) |
|
|
|
|
|
|
|
|
Unconjugated (mg/dL) | 1.5 | 0.8 | 0.7 | 0.5 | 1.1 | 0.6 | 0.45 | 0.67 |
AST (U/L) | 46 | 43 | 35 | 33 | 34 | 38 | 39 | 32 |
ALT (U/L) | 43 | 44 | 37 | 32 | 36 | 40 | 36 | 34 |
Serum alkaline phosphatase (U/L) |
|
|
|
|
|
|
|
|
S. Na+ (mmol/L) | 134 | 145 | 142 | 138 | 142 | 140 | 139 | 138 |
S. K+ (mmol/L) | 2.7 | 3.8 | 4.1 | 4.3 | 4.0 | 3.9 | 4.1 | 3.9 |
After about six months since her first admission, she was again admitted with worsening thyrotoxicosis and jaundice, proximal muscle weakness, and fever with chills for 5 days. This time on evaluation she had conjugated hyperbilirubinemia with raised AST/ALT (96 U/L and 61 U/L, resp.) and normal alkaline phosphatase (151 U/L) indicating hepatocellular injury along with a high total count suggestive of septicemia. No obvious cause for septicemia could be found even after extensive workup. The superimposed septicemia was thought to be the triggering factor for the worsening of her thyroid dysfunction that was initially well controlled with antithyroid drug.
Investigations of the patient at readmission are shown in Table
Investigations of the patient at readmission.
TSH (mIU/L) | < |
Urine R/E | 2–6 pus cells/HPF, RBC-present |
FT4 (ng/dL) (0.89–1.7) |
|
Urine culture | No growth on two occasions |
T3 (nmol/L) (1.25–2.74) | > |
Blood culture | No growth |
TC (total count) (per cm) |
|
X-ray chest PA view | Normal |
DLC (differential leucocytic count) | Neutrophilia | 2D echo | Normal |
Erythrocyte sedimentation rate (ESR) | 106 mm after the end of 1st hour | USG abdomen | Mild hepatomegaly, no evidence of chronic hepatitis, no evidence of cholangitis |
C reactive protein (CRP) (0–10 mg/dL) |
|
||
S. bilirubin (Total) (mg/dL) | 30.2 | ||
Conjugated (mg/dL) | 26.3 | Malaria parasite | Negative |
Unconjugated (mg/dL) | 4.23 | Widal test | Negative |
AST (U/L) |
|
PBS study | No abnormal or immature cells seen |
ALT (U/L) |
|
HBS Ag, anti-HCV |
Negative |
Serum alkaline phosphatase (U/L) | 151 | ANA | 42 IU (weakly positive) |
S. albumin (g/dL) |
|
S. ammonia | Normal |
Prothrombin time (sec) | 15.3 | ||
S. Na+ (mmol/L) | 138 | ||
S. K+ (mmol/L) | 3.1 |
PTU was stopped because of rise in liver enzymes (ALT and AST) keeping in mind the possibility of PTU induced hepatitis. Radioiodine therapy was considered but deferred due to financial constraints. She was started on lithium therapy (300 mg twice daily);
Clinically evident cholestasis with jaundice secondary to uncomplicated hyperthyroidism is rare. Elevated serum alkaline phosphatase is seen in 64% of patients with thyrotoxicosis [
Interestingly our patient presented with reappearance of jaundice at second admission, and this time the biochemical picture was suggestive of a hepatocellular injury rather than a cholestatic pattern as evident during the initial presentation. The exact cause of this hepatocellular damage could not be established even after an extensive workup. Although liver biopsy was not attempted in our case because of the general ill health of the patient, an initial negative screening test for anti-nuclear antibody test was presumably against the diagnosis of autoimmune hepatitis which may sometime occur in association with Grave’s disease. Although we had planned for other autoimmune markers which are more specific for autoimmune liver injury like smooth muscle antibodies, antibodies to liver/kidney microsome type1, antimitochondrial antibodies, and perinulear antineutrophil cytoplasmic antibodies, the poor financial condition of the patient forced us to defer these costly investigations. In patients with chronic hepatitis associated with primary biliary cirrhosis (PBC) or chronic autoimmune hepatitis, there is an increased prevalence of autoimmune thyroid disease [
Our patient was effectively being controlled with a minimum dose of propylthiouracil (PTU) during her follow-up after the initial presentation. Increased serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) may be present in about 30% of patients treated with propylthiouracil [
The uncontrolled hepatocellular damage in our patient may also be a part of a multiorgan dysfunction (MODS) which occurred in association with septicemia due to an unknown cause [
Our patient also developed an acute paraplegia with profound lower extremity weakness and areflexia at second admission during the course of her hospital stay. A nerve conduction study was suggestive of a mixed axonal and demyelinating polyneuropathy. The association of generalized peripheral neuropathy with thyrotoxicosis is rare. However, an acute neuropathy associated with paraplegia or quadriplegia has been described. The presentation has been described as Basedow’s paraplegia by Joffroy in 1891 [
Since we cannot arrive at the exact etiology of hepatic dysfunction with our limiting resources and facilities, we try to treat the patient aiming at all possible mechanisms of liver injury in a patient with Grave’s disease like stopping of the probable antithyroid drug causing hepatitis (PTU) and replacing it with other medications to control the thyrotoxicosis, namely, lithium,
Hepatic dysfunction in a patient with thyrotoxicosis is not an uncommon presentation. But sometimes this simple biochemical abnormality may dominate the clinical picture and complicate the course of the primary disease. It is also evident that although multiple mechanisms may play their roles in development of hepatic dysfunction in a patient with thyrotoxicosis, it is sometimes difficult to establish definitely which factor is causing liver injury in a particular patient. It is probably impractical to separate and find all these causes out, and what seems more important is to focus on definitive treatment directed at saving both these two vital organs using a multidisciplinary approach. Presence of life threatening sepsis should always be carefully sought for in such clinical presentations and if present it should aggressively be treated. Sometimes it becomes very difficult to help such kind of patients even after our best possible efforts, particularly in a developing country like India where access to radioiodine ablation and liver transplantation may not be possible to all groups of patients. It is the need of time to formulate some specific guidelines for managing patients of thyrotoxicosis presenting with severe hepatic dysfunction with special emphasis on those situations where definitive therapy in the form of radioiodine ablation may not be feasible.
The authors declare that there is no conflict of interests regarding the publication of this paper.