Case report

1
Case report

• 2004/9/30
• ENDOCRINE
• Intern 2
• ???

2
Basic data

• NameYang x-Mei
• Age22
• Gender female
• Admission date93/9/24
• Admitted fromOPD

3
Chief complaint

• Skin jaundice and poor appetite were noted from 3
  Days before admission.

4
Present illness

• Patient is a 22-year-old single Minnan Taiwanese
  woman, a student with a history of Graves'
  disease.
• According to the statement, she has had history
  with Graves' disease s/p bil. subtotal
  thyroidectomy on 87-03. She regular follow up at
  OPD for thyroid. She was started anti-thyroid
  agent since half year ago.

5
Present illness

• 93/09/17she came to our ER due to dizziness and
  nausea for several days,scleraicteric,GOT342,liv
  er echomild fatty liver.
• Then she came to the OPD for follow up liver
  function and skin jaundice was noted. At OPD, the
  Bil D/T increased to 3.90/4.27. Under the
  impression of hepatitis caused to be determined
  so she is admitted.

6
Personal history

• Drinking(??)No
• Smoking(??)No
• Betel NutNo
• OperationYes,bilateral subtatal thyroidectomy
  and right humeral fracture s/p op

7
Physical Exam

• General appearance acute ill-looking and mild
  malaise
• Consciousness E4M6V5
• Vital sign TPR 36.8/112/18 BP 122/73 mmHg
• HEENT conjunctiva pale (-)
• sclera mild icteric
• neck supple, no LAP, no JVE
• thyroid impalpable
• Chest symmetric expansion, bilateral coarse
  breathing
• Heart RHB
• Abdomen soft and flat no tenderness,clay
  stool()
• Extremity freely movable
• Skin dry skin turgor
• mild jaundice

8
Impression

• Graves' disease with thyrotoxicosis
• Hepatitis cause to be determined
• Liver function impaired

9
Plan

• Discontinue Procil use
• Increased Inderal dose
• Support care
• Consult G-I man for evaluation jaundice
• Explain condition to patient and families

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Lab
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Lab
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Lab
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Lab
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Lab
15
Lab
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Lab
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Lab
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Lab
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Liver echo report

• Mild fatty liver
• heterogenous pattern over left lobe , cause to be
  determined r/o focal fatty change or early
  abscess ?
• need clinical correlation , suggest f/u or
  further study

20
Clinical course

• 9/25jaundice and appetite improved.
• no other special complaint.
• 9/27bilirubin D/T1.55/1.76, GOT279, GPT198.
• Because her jaundice and liver function improved
  so she was discharged on 9/27 and arrange OPD
  follow up.

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• Fifty Years of Experience with Propylthiouracil-As
  sociated Hepatotoxicity What Have We Learned?

KATHERINE V. WILLIAMS, SUNIL NAYAK, DOROTHY
BECKER, JORGE REYES,AND LYNN A. BURMEISTER
Division of Endocrinology and Metabolism,
Departments of Medicine (K.V.W., L.A.B.) and
Pediatrics (S.N., D.B.), and The Thomas E. Starzl
Transplantation Institute (J.R.), University of
Pittsburgh School of Medicine, Pittsburgh,
Pennsylvania 15261
22
ABSTRACT

• The aim of this study was to determine the
  optimal managementof patients with
  propylthiouracil (PTU) hepatotoxicity.
• A MEDLINE search for English language cases of
  PTU hepatotoxicity between 1966 and April 1996
  was performed, and additional cases were
  cross-referenced.
• Twenty-seven cases were selected based on the
  availability of information on patient management
  after the onset of hepatotoxicity.

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ABSTRACT

• Although most patients recovered once PTU was
  stopped, seven patients died.
• Patients with PTU hepatotoxicity who survived
  were more likely to have received 131I during the
  course of their illness than those who died
• In our two patients,hyperbilirubinemia was
  linearly associated with progressively decreasing
  T4 levels despite the presence of clinical
  thyrotoxicosis in one of the patients.

24
ABSTRACT

• These findings demonstrate the need for
  appropriate clinical evaluation and treatment of
  thyroid disease during the course of
  hepatotoxicity
• The emerging role of liver transplantation in
  these patients is discussed.

25
Discussion

• PTU-associated hepatotoxicity is a rare and
  life-threatening complication of anti-thyroid
  drug treatment of hyperthyroidism.
• Estimated incidenceless than 0.5(true incidence
  is unknown)
• PTU hepatotoxicity occurs at all ages and, like
  thyroid disease , shows a female predominance.
• The ranges for both PTU dose and duration of
  therapy in the patients who developed
  hepatotoxicity are wide.

26
Discussion

• The presentation of PTU hepatotoxicity is
  clinically nonspecific.
• Abnormalities or worsening of liver function
  tests suggest the diagnosis. However,a search for
  other potential causes of hepatic dysfunction
  remains necessary.

27
Discussion

• The mechanism of antithyroid drug hepatotoxicity
  is not known,although positive lymphocyte
  sensitization studies in some patients who
  developed PTU hepatotoxicity suggest an immune
  reaction to PTU

28
Discussion

• Because both hyperthyroidism and hepatic
  dysfunction may progress despite discontinuation
  of PTU, appropriate management of both diseases
  is critical.
• Upon recognition of hepatotoxicity, PTU should be
  discontinued.

29
Discussion

• With supportive therapy, most patients should
  recover. However, death due to complications of
  liver failure occurred in 25 of the population
  reported herein
• Thus,early recognition of fulminant hepatic
  failure and intervention may be necessary.

30
Discussion

• Several early prognostic factors are known to be
  associated with survival rates of less than 20
  in fulminant hepatic failure
• These include patient age (lt11 and gt40 yr),
  duration of jaundice (gt7 days) before the onset
  of encephalopathy, serum bilirubin concentration
  (gt300 mmol/L), and prothrombin time (gt50 s).

31
Discussion

• The etiology of fulminant hepatic failure may be
  the most important variable predicting outcome in
  medically managed patients, with a survival rate
  of only 13.6 in patients with idiosyncratic drug
  reactions
• If patients who receive a liver transplant are
  included in this group, the overall survival rate
  is increased to 2030
• Early referral to a transplantation center may
  improve the chances of finding a suitable donor
  organ

32
Discussion

• The presence of encephalopathy,
  hypoprothrombinemia, or the hepatorenal syndrome
  may hasten the need for transplantation
• Lastly, plasmapheresis or hemodialysis with
  hemoperfusion for correction of coagulopathy and
  encephalopathy may be effective in providing time
  for recovery of the liver or as a bridge to
  transplantation

33
Discussion

• Interactions between both thyroid and hepatic
  disease as well as the patients clinical status
  must be considered
• Acute hepatitis may increase the concentration of
  thyroid hormone binding globulin, causing an
  increase in the total T4 level and a decrease in
  the thyroid hormone binding ratio

34
Discussion

• With progressive hepatic dysfunction, the
  interaction between thyroid and hepatic disease
  becomes even more important.
• Bilirubin may also have interfered with the
  measurement of T4 by lowering the affinity of T4
  for thyroid hormone-binding proteins
• Both cases presented showed an inverse linear
  relationship between total T4 level and serum
  bilirubin(Fig. 1).

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Fig.1
36
Discussion

• Furthermore, because bilirubin is a marker of the
  severity of hepatic dysfunction, the correlation
  between bilirubin and total T4 may only reflect
  the progression of nonthyroidal illness
• Because free T4 may be elevated when total T4 is
  normal, low, or unmeasurable in hyperthyroidism
  associated with severe illness, the measurement
  of free T4 levels may aid in the interpretation
  of the patients thyroidal status.

37
Discussion

• The options for treatment of hyperthyroidism in
  such patients are limited.
• The majority of patients received definitive
  treatment with 131I, and this form of treatment
  was significantly associated with survival.
• It is possible that patients treated with 131I
  had a less severe form of hepatotoxicity than the
  patients who did not receive treatment,thus
  reflecting selection bias

38
Discussion

• Nevertheless, the ideal treatment may be
  immediate 131I therapy when PTU hepatotoxicity is
  suspected.
• The use of iodide alone after recognition of
  hepatotoxicity merits further comment.
• In most patients, iodide doses of 114 mg produce
  maximal suppression of thyroid hormone levels
  within 714 days and last from 1 to more than 50
  days

39
Discussion

• Because iodide can also provide substrate for
  thyroid hormone synthesis, it is usually used in
  combination with antithyroid drugs
• However, because the cause of hyperthyroidism is
  variable (Graves disease vs. toxic multinodular
  goiter), this therapy cannot be recommended in
  all patients.

40
Discussion

• An important question that could not be answered
  by this study is whether patients with
  preexisting liver function test abnormalities or
  hepatic disease are at increased risk of
  developing hepatotoxicity.
• PTU has been administered in a clinical trial to
  patients with alcoholic hepatitis with associated
  decreased mortality and without reported
  worsening of liver function.

41
Discussion

• Up to 72 of patients with hyperthyroidism and
  presumably normal liver function may have an
  elevation of at least one hepatic enzyme
• Alkaline phosphatase elevations are most commonly
  reported

42
Discussion

• In one prospective study, thyrotoxic patients
  with mild baseline alanine aminotransferase (ALT)
  elevations had either an increase or a decrease
  in ALT with PTU treatment. When PTU was continued
  at a reduced dose, ALT levels normalized in most
  patients
• Marked baseline elevations in liver enzymes
  require investigation for underlying liver
  disease.

43
Discussion

• This report does not include data on methimazole
  hepatotoxicity,for which there have been 21
  reported cases and 3 reported deaths
• The percentage of deaths from methimazole
  hepatotoxicity did not reach statistical
  significance compared to the percentage of
  reported deaths in patients with PTU
  hepatotoxicity

44
Discussion

• In summary, in the past 50 years there have been
  several changes that can affect the management of
  PTU-associated hepatotoxicity, including
  improvements in thyroid hormone assays,
  additional forms of anti-thyroid therapy, and
  liver transplantation
• No specific factors identify the risk of
  hepatotoxicity in an individual patient.
• Recommendations for the management(table 5)

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46
Discussion

• Baseline hepatic function abnormalities may be
  related to hyperthyroidism and do not necessarily
  contraindicate the use of antithyroid drugs.
• If significant hepatic enzyme abnormalities
  develop during the course of PTU therapy, the
  drug should be discontinued immediately, and
  definitive treatment of the hyperthyroidism
  should consist of 131I therapy

47
Discussion

• Because of the possible autoimmune etiology of
  PTU hepatotoxicity and recurrence of
  hepatotoxicity with drug rechallenge , PTU should
  not be reinstituted even after resolution of
  hepatotoxicity or liver transplantation.
• Appropriate evaluation of the patients thyroid
  status requires assessment of both physical
  findings and accurate measurement of free T4
  levels.

48
Discussion

• Close clinical follow-up is necessary because
  hepatic failure can progress despite
  discontinuation of PTU.
• Recognition of the need for liver transplantation
  and prompt referral to a transplant center may be
  lifesaving.
• Using these combined approaches it is possible
  that deaths from PTU-associated hepatotoxicity
  might be reduced over the next 50 years.

49

• The Incidence and Clinical Characteristics of
  Symptomatic Propylthiouracil-Induced Hepatic
  Injury in Patients With Hyperthyroidism A
  Single-Center Retrospective Study

Hee-Jin Kim, Byung-Ho Kim, Yo-Seb Han, Inmyung
Yang, Kyeong-Jin Kim, Seok-Ho Dong, Hyo-Jong Kim,
Young-Woon Chang, Joung-Il Lee, and Rin Chang
Department of Internal Medicine, Kyung Hee
University College of Medicine, Seoul, Korea
50
OBJECTIVES

• Although symptomatic propylthiouracil(PTU)-induced
  hepatic injury is known to be rare, there have
  been few reports about its exact incidence in
  patients with hyperthyroidism.
• We tried to evaluate its incidence in a single
  center and its clinical course.

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METHODS

• Medical records of 912 hyperthyroid patients who
  had been diagnosed between March 1990 and
  December 1998 were reviewed about clinical
  characteristics, management, and laboratory
  findings.
• Symptomatic PTU-induced hepatic injury was
  defined as the development of jaundice or
  hepatitis symptoms with at least a 3-times
  elevation of liver function tests (LFT) without
  other causes.

52
RESULTS

• Four hundred ninety-seven patients (age 42.6 -
  10.7 yr, male/female 140/357) were included
• Hepatitis developed in six patients between 12
  and 49 days after PTU administration.
• Jaundice and itching developed in five patients
• Bilirubin, ALT, and ALP increased in five, four,
  and six patients, respectively (293 6 288 mmol/L,
  143 6 111 U/L, and 265 6 81 U/L normal, ,117
  U/L).

53
RESULTS

• The type of hepatic injury was cholestatic in
  three, hepatocellular in one, and mixed in two
  patients.
• None resulted from viral hepatitis.
• There were no statistical differences in age,
  sex, PTU dose, or T4 and T3 levels at initial
  diagnosis between patients with and without
  hepatic injury.
• LFT normalized in all patients between 16 and 145
  (72.8 6 46.4) days after the PTU withdrawal.

54
CONCLUSIONS

• Symptomatic hepatic injury develops usually
  within the first few months of PTU administration
  with rare frequency, but its clinical course is
  relatively benign once the drug is withdrawn.
• However, it may be difficult to predict its
  development, so all patients should be monitored
  for rise in LFTs at regular intervals, especially
  during the early period.

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Thanks for your attention