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

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

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.

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.

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

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

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

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

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

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

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

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

Hematologic tests on admission

Item Value

WBC (/mm3) 13,900

Band forms -

Neutrophils -

Lymphocytes -

Hemoglobin (g/mL) 7.3

Platelets (/mm3) 27,1000

Biochemical tests on admissionItem 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

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.

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)

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

Day zero

Electrocardiogram

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

The story continues: 1st week of hospital stay

BP

Day 1

First week of hospital stay

BP

Antibiotics are SOCIETAL drugs of :FEVER, FEAR, PROMOTION, and PROPHYLAXIS.

Echo abdomenVancomycin 1g stat

Flumarin day 2 Flumarin day 3 Flumarin day 4 Flumarin day 5

Diagnostic ascites tapping

Flumarin 1g day 1

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

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

Ultrasonographic study

1. D-56

• Fatty liver

• Gallbladder polyps and small stones

2. D7

o Normal liver

o Gall stones

o Peripancreatic lymphadenopathy

Computed tomography

D7

aa

“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

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

Laboratory tests on D60

• Copper 147 µg/dL (Ref. 70-140)

• Ceruloplasmin > 79.7 mg/dL (16-35)

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)?

Glim, piog, amlo, vals; mino, cefa, cefu, acet (D-163~-127)Melo (D-150~-61), biso (D-118~-16); marc, lido, mepe, morpMida, esta (-141), flun, ator, cila

The trends of LFTs and prior medications

Medications on D-150

1. Glimepiride

2. Pioglitazone

3. Amlodipine

4. Acetaminophen

5. Meloxican

6. Cefuroxime

7. Minocycline

8. Estazolam

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-reportgenetics, complexity, latency, chronicity

How to investigate DILIDr. 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”

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

The candidate drugs cause this patient’s liver injury

1.Hepatitis: acetaminophen2.Cholestasis without hepatitis

• Glimepiride3.Cholestasis with hepatitis

• Glimepiride, meloxican, atorvastatin4.Cholestasis with bile duct injury

• Pioglitazone5.Vanishing bile duct syndrome: diazepam

Two drugs given before D-130, when LFTs normal and asymptomatic

Alkaline phosphatase

Alanine aminotransferase

Accumulative dose of meloxican

aaaaaaaaaaaaaaAccumulative dose of acetaminophen

ALP

ALT

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