Drug-related diseases are prevalent, but may be insidious. Drs treat patients with medication; sometimes, unintentionally they drug their patients, or even kill them.

1. A 58 year-old male shoemaker
with yellow and itchy skin for
2 months
Yueh-Ren Ho Ph.D, Chien-Ming Li MD, Ph.D

2. The patient
• A 58 years old male shoemaker
• A nonsmoker, nondrinker
• Type 2 diabetes mellitus for 10 years
• Hypertension for 5 years
• Hemodialysis for 9 months

3. The story
• The 58-year-old man is hospitalized because
of skin itching and yellowish discoloration
started around 2 months earlier with
progressive fatigue, and decreased appetite.
• He denied having fever, chills, night sweats,
abdominal pain, diarrhea, melena, or
hematochezia.

4. Narrative medicine: present illness
• This hypertensive diabetic started
hemodialysis 9 months ago.
• Four months later, he encountered a fall and
broke his femur bone that had been fixed at
this hospital.
• There is none of bruising, spider angiomas,
gynecomastia, testicular atrophy, and palmar
erythema.

5. Hospitalization one year earlier (1)
• Chief complaint: legs edema for 2 months
• PI: worsening breathlessness for 1 week
• The vitals: 38.5 degrees Celsius/91 bpm/22 breaths/min;
BP 172/108 mm Hg
• Lab tests: BUN/Cr 68-99/7.9-9.1 mg/dL
Hb 6.7-8.8 g/mL
ALT (alanine aminotransferase) 24 IU/L

6. Hospitalization one year earlier (2)
• Ultrasonographic kidney length: 8.2/8.8 cm
• Dx: diabetic nephropathy at end stage,
hypertension, diabetes retinopathy
• Rx: amlodipine 5mg qd

7. The 2nd hospital admission 5 mo. earlier
• Left-side femoral neck fracture
• Results of laboratory tests
1. AST (aspartate aminotransferase) 22 IU/L
2. ALT (alanine aminotransferase) 15 IU/L
3. ALP (alkaline phosphatase) 104 IU/L
4. Total bilirubin 0.2 mg/dL

8. Summary of medical history
• -12 months
Uremic syndrome, diabetes, hypertension
• -11 months
AV fistula creation
• -5 months
Fall and left-side femoral neck fracture
• -2 months: skin itching  yellow skin

9. The presentations and medications
on outpatient clinics
• Day -60: dermatitis, hepatitis
• Day -50: extrapyramidal and movement disorder
• Day -40: dyslipidemia
• Day -30: jaundice
• Day -25: legs weakness, hand tremor; cilastazol
• Day -15: jaundice
• Day -7: ursodiol, dimeticone, pioglitazone,
glimepiride, lorazepam

10. The medications given 2 months earlier
1. Glimepiride 1mg qd
2. Pioglitazone 30mg qd
3. Amlodipine 5mg qd
4. Valsartan 80mg qd
5. Nifedipine oros 30mg
6. Bisoprolol 5mg hs
7. Meloxicam 15mg qd
8. Atorvastatin 40mg qod
9. Desloratadine 5mg qd
10. Flunitrazepam 1mg hs

11. Biochemistry before hospitalization
Time
(day)
AST
(IU/L)
*ALT
(IU/L)
*ALP
(IU/L)
Bilirubin
(direct; mg/dL)
GGT
(IU/L)
-60 72 126 329 1.99 594
-40 133 102 519 6.52
-30 122 83 546 9.27 540
0 102 99 596 18.81 478
*ALT/ALP = 0.2

12. Physical examination on admission
• Postdialysis weight was 58 kg; 168 cm tall
• TPR: 37.5°C/80/20; BP: 133/54 mm Hg
• General appearance: alert, oriented
• Skin and sclerae: yellow and icteric
• Murphy sign absent
• Lung, hear, and abdomen: normal

13. Hematologic tests on admission
Item Value
WBC (/mm3) 13,900
Band forms -
Neutrophils -
Lymphocytes -
Hemoglobin (g/mL) 7.3
Platelets (/mm3) 27,1000

14. Biochemical tests on admission
Item Value
AST/ALT (IU/L) 106/97
GGT
(γ-glutamyl transpeptidase; IU/L)
478
ALP (IU/L) 596
Direct bilirubin (mg/dL) 20
Albumin (g/dL) 3.0
Fasting glucose/A1c (mg/dL; %) 112/7.0
Na/K/Ca (mEq/L; mg/dL) 135/3.6/8.2

15. Family, social and travel history
1. He had no FH of cancer or liver disease.
2. He did not smoke and not drink alcohol.
3. He had never used recreational drugs.
4. He had not traveled recently and had not
been exposed to any pet or animals.

16. He did not use Chinese herbal medicines
1. Xiao Chai Hu Tang (小柴胡湯)
1) Bupleurum falcatum(柴胡)
2) Scutellaria baicalensis (黃芩)
2. Ephedra sinica(草麻黃)
3. Tripterygium wilfordii (雷公藤)
4. Radix chloranthi serrati (及己)
5. Galla chinensis (五倍子)
6. Fructus toosendan (川揀子)

17. Retrospective biochemical tests: direct
bilirubin and alkaline phosphatase
Time
(day)
AST ALT ALP Bilirubin
(direct )
GGT
-90 53 98 303 0.3
-65 72 126 296 1.1
-60 329 2.0 594
-35 119 102 519 6.5 643
-30 122 83 456 9.3 540
-15 101 67 596
-2 106 97 19.7
0 102 99 570 20 478

18. Day zero

19. Electrocardiogram

20. Diagnosis and plan
S: skin itching for 2 months
yellowish discoloration for 1 month
O: jaundice for one month
elevation of LFTs for longer than 3 months
A: hepatitis, direct hyperbilirubinemia
Chronic ills: 250, 401, 585
P: searching for the etiology, explanation, Rx

21. The story continues: 1st week of hospital stay
BP
Day 1

22. First week of hospital stay
BP
Antibiotics are SOCIETAL drugs of :
FEVER, FEAR, PROMOTION, and PROPHYLAXIS.
Echo abdomen
Vancomycin 1g stat
Flumarin day 2 Flumarin day 3 Flumarin day 4 Flumarin day 5
Diagnostic
ascites tapping
Flumarin 1g day 1

23. Serology and immunology I
• HBsAg Absent
• Anti-HBsAb Absent
• Anti-HBc IgM Absent
• Anti-HAV IgM Absent
o AFP: 3 ng/mL
o CEA: 6.2 ng/mL
o CA199: <2 U/mL

24. Serology and immunology III
• Anti-nuclear antibody (ANA) Absent
• Anti-smooth muscle Ab Absent
• Anti-mitochondrial Ab Absent
• Anti-neutrophil cytoplasmic Ab Absent
• Anti-ds DNA Absent
• Anti-Ro Ab (SSA) Absent
• Anti-La Ab (SSB) Absent

25. Ultrasonographic study
1. D-56
• Fatty liver
• Gallbladder polyps and small stones
2. D7
o Normal liver
o Gall stones
o Peripancreatic lymphadenopathy

26. Computed tomography
D7
aa

27. “Deduction is reasoning backward”
Time
(day)
AST ALT ALP Bilirubin
(direct )
GGT
-150 22 15 104 0.1
-130 45 66 223 0.2
-90 53 98 303 0.3
-65 72 126 296 1.1
-60 329 2.0 594
-35 119 102 519 6.5 643
-30 122 83 456 9.3 540
-15 101 67 596
0 102 99 570 20 478

28. The trends of the LFTs
Time (day)
D-130
Hospitalization
Jaundice
"Data! Data! Data!“ he cried
impatiently. "I can't make bricks
without clay.“
-The Adventure of the Copper
Beeches

29. Laboratory tests on D60
• Copper 147 µg/dL (Ref. 70-140)
• Ceruloplasmin > 79.7 mg/dL (16-35)

30. Arterial blood gas on D60
As breathing the ambient air
• pH 7.12
• PCO2 32
• PO2 62
• Bicarbonate 11
• Base excess -18
o Cause of death (COD)?

31. Glim, piog, amlo, vals; mino, cefa, cefu, acet (D-163~-127)
Melo (D-150~-61), biso (D-118~-16); marc, lido, mepe, morp
Mida, esta (-141), flun, ator, cila
The trends of LFTs and prior medications

32. Medications on D-150
1. Glimepiride
2. Pioglitazone
3. Amlodipine
4. Acetaminophen
5. Meloxican
6. Cefuroxime
7. Minocycline
8. Estazolam

33. Drug-induced liver injury (DILI)
1. Mimic primary liver disease: histology
2. Inadequate clinical history and human mind
1) Onset of liver disease following Rx
2) Multiple drugs involved
3) Herbal agents: HILI
4) Over-the-counter medications
5) Household, occupational or industrial toxins
Unpredictable/idosyncratic : under-report
genetics, complexity, latency, chronicity

34. How to investigate DILI
Dr. Dame Sheila Sherlock
1. Suspect any drug
2. Detail drug history
3. De-challenge: fall of LFTs
4. Re-challenge
5. Exclude other liver disease
Viruses, autoimmune, obstruction
6. Biopsy “When you have eliminated the impossible, whatever remains,
however improbable, must be the truth?“
“The Sign of Four”

35. Classification of drug-induced
cholestatic syndrome (DICS)
1. Intrahepatic
1) Acute: +/- hepatitis , bile duct injury
2) Chronic
a. Mild bile duct injury
b. Vanishing bile duct syndrome (VBDS)
c. Primary sclerosing cholangitis-like
2. Extrahepatic
1) Cholelithiasis
2) Primary sclerosing cholestasis

36. The candidate drugs cause this
patient’s liver injury
1.Hepatitis: acetaminophen
2.Cholestasis without hepatitis
• Glimepiride
3.Cholestasis with hepatitis
• Glimepiride, meloxican, atorvastatin
4.Cholestasis with bile duct injury
• Pioglitazone
5.Vanishing bile duct syndrome: diazepam

37. Two drugs given before D-130, when
LFTs normal and asymptomatic
Alkaline phosphatase
Alanine aminotransferase
Accumulative dose of meloxican
aaaaaaaaaaaaaa
Accumulative dose of acetaminophen
ALP
ALT

38. 當病人的問題你無法解釋時
請逐項考慮 Pathophysiology
1. Drugs
2. Dose
3. Duration
4. Diagnosis
5. Drain
6. Debridement
7. Death