BY:

DR.FAIZA RESIDENT MEDICAL UNIT 4 CHK.

BIODATA
Name Husband name Age Sex Marital status D.O.A M.O.A Najma Zaheer Ahmad 27 Y Female Married May 12, 2011 Emergency

PRESENTING COMPLAINTS
Yellowish discoloration of Sclera and body since 15 days

HISTORY OF PRESENTING COMPLAINS

According to the patient she was in usual state health of 15 days back then she developed yellowish discoloration of sclera followed by yellowish discoloration of body. This was associated with nausea and vomiting but not associated with puruitis, pale stools, malena, hematemesis, abdominal pain, ALOC.

According to her she noticed this yellowish discoloration after taking some medication for vaginal discharge that she developed after an abortion one month prior. She developed nausea and vomiting soon after starting the medication that was prescribed by a local GP.

HISTORY OF PRESENTING COMPLAINS (contd) For these complaints she visited a hospital but the problem did not settle and the jaundice became more worse over the following days for which she was referred to CHK.

SYSTEMIC REVIEW:
Gastrointestinal system: No Epigastric pain, no diarrhea or constipation Respiratory system: No SOB,no cough, no chest pain. CVS: No PND, orthopnea, pedal edema, central chest pain or any other complains. CNS: no dizzy spells, blackouts, headache,no gait or speech abnormality, vertigo or any other complains. Genitourinary: No complains. Musculoskeletal: No complains of joint pains.

PAST MEDICAL HISTORY:

Nothing Significant History of vaginal discharge 2 weeks prior to Jaundice Before this, she aborted a seven weeks old fetus almost a month back

PAST SURGICAL HISTORY:

Nothing significant

DRUG HISTORY:
As already mentioned. Can not specify the name.

HISTORY OF BLOOD TRANSFUSION:

None

PERSONAL HISTORY:
Appetite Sleep Bowel habits Micturition Addiction Weight loss Decreased Disturbed Normal Normal None Present

FAMILY HISTORY:
Husband Alive and Healthy A 3 years old baby boy, NVD No history of any fimalial disease running in the family

SOCIO ECONOMIC HISTORY:

Low income family

EXAMINATION

VITALS ( ON ADMISSION):
BP Pulse R/R Temp 110/70 80 20 A/F

GENERAL PHYSICAL EXAMINATION

Anemia Jaundice Clubbing Cyanosis Pedal Edema Koilonychia Dehydration Lymph nodes Palmar erythema Spider naevi Thyroid JVP

Nil +++ Nil Nil Nil Nil Nil Not palpable Nil Nil Not enlarged Not raised

ABDOMINAL EXAMINATION
INSPECTION: Moving equally with respiration, no scar marks, pigmentations. PALPATION: Soft and non tender
Liver not palpable, liver span 8 cms Spleen not palpable Kidneys and Abdominal Aorta not palpable. PERCUSSION: No signs of free fluid AUSCULTATION: Gut sounds audible

RESPIRATORY SYSTEM
No pigmentation or scars noted. Moving equally with respiration. On auscultation normal vesicular breathing with no added sounds.

CARDIOVASCULAR SYSTEM
H/R: 80/min & regular, No radio-radial or radiofemoral delay on comparison of pulses. APEX BEAT: 5th intercostal space medial to mid clavicular line. S1 & S2 audible , no murmur heard in all 4 areas.

CENTRAL NERVOUS SYSTEM

HMF SPEECH & GAIT SOMI CRANIAL NERVES PUPILS CEREBELLAR SIGNS Intact Normal Negative Intact BERLA Negative

MOTOR SYSTEM:
Right upper limb BULK TONE POWERS REFLEXES Normal Normal 5/5 Normal Right lower Left upper limb limb Normal Normal 5/5 Normal Normal Normal 5/5 Normal Left lower limb Normal Normal 5/5 Normal

PLANTARS

___

Down going

___

Down going

SENSORY SYSTEM:

Pain & temperature Fine touch Vibration Joint position & proprioception

Intact Normal Normal Intact

CASE SUMMARY
Najma, w/o Zaheer Ahmad, 27, resident of model colony presented with complaints of discoloration of sclera and body for 15 days that was associated with nausea, vomiting but not associated with puruitis, pale stools, malena, hematemesis, abdominal pain, ALOC. History of drug intake two weeks back for vaginal discharge. on examination vitally stable. No organomegaly, no peripheral stigmata of chronic liver disease noted.

DIFFERENTIAL DIAGNOSIS

Differential Diagnosis
Acute Viral Hepatitis

Drug Induced Hepatitis

Cholestasis secondary to drugs.

INVESTIGATIONS

CBCs HB MCV TLC Platlets PT APTT INR

12/5 10.20 94.30 6300 149000 24/13 55/36

13/5 9.10 96 6700 131000 20 40 1.62

16/5 9.3 97.40 6800 128000

21/5 9.9 101.00 1300 129000 15.3 32.4 1.4

LFTs Total Bili Direct Bili Indirect Bili

12/5 76.46 41.20 35.26

13/5 65.79 35.90 29.89

13/5 59.89 53.40 6.49

16/5 58.3 31.78 26.25

20/5 50.15 27.70 22.45

21/5 38.88 21.16 17.72

SGPT

425

226

290

95

71

53

ALK. Phos

87

67

90

65

58

73

UCE Na K Cl BUN Cr

12/5 135 2.7 95 11 1.1

13/5 140 2.9 105 4 0.8

16/5 138 2.7 104 5 0.9

20/5 136 2.6 102 4 0.9

 Fasting blood sugar

92mg%

VIRAL MARKERS:
HBsAg & Anti HCV Anti HEV & anti HAV Non reactive Awaited

A/G RATIO:
Total proteins Albumin Globulin A/G ratio 5.6 gm/dl 3.8 gm/dl 1.8 gm/dl 2.1

U/S ABDOMEN
Liver normal in size measuring 14.8 cm with subtle coarse eco-texture, intra hepatic and biliary ducts are not dialated, portal vein 1.1 cm, free fluid not present. Spleen normal in size and shape measuring 12.1 cms. Rest of the scan is Normal.

Evaluation of Abnormal Liver Function Tests

Markers of Hepatocellular damage (Transaminases)

AST- liver, heart skeletal muscle, kidneys, brain, RBCs
In liver 20% activity is cytosolic and 80% mitochondrial Clearance performed by sinusoidal cells, half-life 17hrs

ALT more specific to liver, v.low concentrations in

kidney and skeletal muscles. In liver totally cytosolic. Half-life 47hrs

 Gamma-GT hepatocytes and biliary epithelial

cells, pancreas, renal tubules and intestine Very sensitive but Non-specific Raised in ANY liver discease hepatocellular or cholestatic Usefulness limited Confirm hepatic source for a raised ALP Alcohol Isolated increase does not require any further evaluation, suggest watch and rpt 3/12 only if other LFTs become abnormal then investigate

Markers of Cholestasis
ALP liver and bone (placenta, kidneys, intestines or
WCC) Hepatic ALP present on surface of bile duct epithelia and accumulating bile salts increase its release from cell surface. Takes time for induction of enzyme levels so may not be first enzyme to rise and half-life is 1 week. ALP isoenzymes, 5-NT or gamma GT may be necessary to evaluate the origin of ALP

Bilirubin, Albumin and Prothrombin time (INR)

Useful indicators of liver synthetic function In primary care when associated with liver disease abnormalities should raise concern Thrombocytopaenia is a sensitive indicator of liver fibrosis

Transaminases
May not be elevated in chronic liver disease
HCV- apoptosis Cirrhosis

Minimal ALT elevations (<1.5 X normal)

Race/Gender Obesity Muscle injury

Mild Transaminitis
AST/ALT < 5 times upper limit of normal Etiologies
Hepatic: ALT-predominant

Chronic Hep C Hemochromatosis Chronic Hep B Medications/Toxins Acute viral hep Autoimmune Hep Steatosis Alpha1 Antitrypsin Def Wilsons Disease Celiac Disease

Mild Transaminitis
Hepatic: AST predominant
Alcohol Steatosis Cirrhosis

Non-hepatic
Hemolysis Myopathy Thyroid disease Strenuous exercise

Elevated AST & ALT, <5X normal Hx & physical; stop hepatotoxic meds

LFTs, PT, albumin, CBC, Hep A/B/C, Fe, TIBC, Ferritin

Serologies: HAV IgM HBsAg HBcIgM HCV Ab or RNA

Negative serology, asymptomatic

Negative serology

Positive serology

Hepatotoxic Medications
Analgesics- acetaminophen, NSAIDS Antimicrobials
Amox-clav, nitrofurantoin, sulfonamides INH Azoles Protease Inhibitors

Anticonvulsants- carbamazepine, valproic acid, phenyton

Hepatotoxic Medications
Cardiovascular- alpha-methyldopa, amiodarone, labetalol Hyperglycemics- glyburide, troglidazone Psychiatric- trazadone, disulfiram Heparin Propylthiouracil Statins Zafirlukast Dantrolene, Halothane, Nicotinic acid, Phenylbutazone

Hepatotoxic Herbals
Chaparral leaf Ephedra Gentian Germander Jin Bu Huan Senna, Kavakava Scutellaria (skullcap) Shark cartilage Vitamin A

Negative Serology- Asymptomatic

Stop EtOH & meds; wt loss; glucose control
6 months

Abnormal

Repeat LFTs

Normal

Ultrasound, ANA, smooth muscle Ab, ceruloplasmin, antitrypsin, gliadin & endomysial Ab Liver biopsy

Observation

Negative Serology- Clinical Signs/Symptoms of Liver Disease

Consider ultrasound, ANA, smooth muscle Ab, ceruloplasmin, antitrypsin
Abnormal

Liver biopsy

Positive Serologies
Hep A IgM + Hep C/B infection Follow clinically, serial LFTs Persistent elevated LFTs > 6 mos

Observation

Clinical improvement, LFTs normalize in <6 mos

Observation

Liver biopsy

 HAV

Serologic Tests for Viral Hepatitis

Hep A IgM- in acute infxn Hep A IgG- in previous infxn or vaccination

HCV
HCV Ab- during or after infection HCV-RNA- during infection

Detectable prior to HCV Ab turning positive

Serologic Tests for Viral Hepatitis

HBV
Hep B Surface Ag- in active infxn Hep B Surface Ab- in prior infxn or vaccinated Hep B Core Ab IgM- in active infxn Hep B Core Ab IgG- in current or prior infxn HBV-DNA- in active infxn Hep B e Ag & Ab- markers of viral presence and potential infectivity

Acute Hepatitis B Virus Infection with Recovery

Typical Serologic Course

Symptoms HBeAg anti-HBe

Total anti-HBc

Titre
HBsAg IgM anti-HBc anti-HBs

12

16

20

24

28

32

36

52

100

Weeks after Exposure

Bilirubin
Product of hemoglobin breakdown 2 Forms
Unconjugated (indirect)- insoluble

in hemolysis, Gilbert syndrome, meds

Conjugated (direct)- soluble

in obstruction, cholestasis, cirrhosis, hepatitis, primary biliary cirrhosis, etc. No elevation until loss of > 50% capacity

Elevated Bilirubin
Unconjugated bili; Normal alk phos, ALT, AST Conjugated bili; Abnormal alk phos, ALT, AST

RUQ u/s to assess ductal dilatation

Hemolysis studies, review meds

+
ERCP or MRCP

ALT eval, review meds, AMA, ERCP or MRCP, liver bx

Other Liver Labs

Albumin
Poor marker of liver function- decreased by trauma, inflammatory conditions, malnutrition

Prothrombin time (PT)

Insensitive: no change until liver loses 80% capacity

Ammonia
No correlation between brain & serum values Only one contributor to encephalopathy

Acute hepatitis (ALT>10xULN)

Viral Ischaemic Toxins Autoimmune Early phase of acute obstruction

Acute hepatitis (ALT>10xULN)

Viral Hep A, B, C, E, CMV, EBV ALT levels usually peak before jaundice appears. Jaundice occurs in 70% Hep A, 35% acute Hep B, 25% Hep C Check for exposure Check Hep A IgM, Hep B core IgM and HepBsAg, Hep C IgG or Hep C RNA

Acute hepatitis (ALT>10xULN)

Ischaemic- sepsis, hypotension ?most common cause in-patients Often extremely high >50x Decrease rapidly LDH raised 80% Rarely jaundiced

Acute hepatitis (ALT>10xULN)

Toxins - paracetamol (up to 50% of all cases of Acute Liver Failure) Ecstasy ( 2nd most common cause in the young <35) Any drug herbal remedies Alcohol almost never, AST <7xULN in 98% AST/ALT ratio > 1 in 92%, >2 in 70%

Acute hepatitis (ALT>10xULN)

Autoimmune Rarely presents with acute hepatitis Usually jaundiced and progressive liver failure Raised IgG and autoantibodies (anti-SM, -LKM, -SLA) Liver biopsy Steroids and azathioprine

Acute hepatitis (ALT>10xULN)

Early phase- extrahepatic obstruction/cholangitis Usually have history of pain USS dilated CBD ? ERCP or lap chole

Alkaline Phosphatase
Produced by biliary epithelial cells
Non-specific to liver: bone, intestine, placenta

Elevations
Biliary duct obstruction Primary biliary cirrhosis Primary sclerosing cholangitis Infiltrative liver disease- ie sarcoid, lymphoma Hepatitis/cirrhosis Medications

Medications
Hormones- anabolic steroids, estrogen, methyltestosterone Antimicrobials- augmentin, erythromycin, flucloxacillin, TMP-SMX, HIV meds Cardiovascular- captopril, diltiazem, quinidine Hyperglycemics- chlorpropamide, tolbutamide Psychiatric- fluphenazine, imipramine, iprindole Others- allopurinol, carbamazepine

Elevated Alk Phos

Normal LFTs, bili Abnormal LFTs RUQ u/s for ductal dilatation

GGT or 5-NNT

Other source
No dilatation

+
RUQ us, med review, AMA

Yes

No

ERCP

AMA
Neg

Observation Liver bx
AP > 6 mo

ALT eval, liver bx, ERCP or MRCP

Cholestasis
Isolated ALP 3rd trimester, adolescents Bone exclude by raised GGT, 5-NT or isoenzymes May suggest biliary obstruction, chronic liver disease or hepatic mass/tumour Liver USS/CT most important investigationdilated ducts Ca pancreas, CBD stones, cholangioca or liver mets

Cholestasis non-dilated ducts

Cholestatic jaundice Drugs- Antibiotics, Nsaids, Hormones, ACEI PBC anti- mitochondrial Ab, M2 fraction, IgM PSC associated with IBD 70%, p-ANCA, MRCP and liver biopsy Chronic liver disease Cholangiocarcinoma beware fluctuating levels Primary or Metastatic cancer, lymphoma Infiltrative sarcoid, inflammatory-PMR, IBD Liver biopsy often required

Investigation of Abnormal LFTs

PRINCIPLES 2.5% of population have raised LFTs Normal LFTs do not exclude liver disease Interpret LFTs in clinical context Take a careful history for risk factors, drugs (inc OTCs), alcohol, comorbidity, autoimmunity Physical examination for liver disease Chase likely diagnosis rather than follow algorithm unless there are no clues If mild abnormalities and no risk factors or suggestion of serious liver disease , repeat LFTs after an interval (with lifestyle modification)

Investigation of Abnormal LFTs ALT/AST 2-5x normal

History and Examination Discontinue hepatotoxic drugs Continue statins but monitor LFTs monthly Lifestyle modification (lose wt, reduce alcohol, diabetic control) Repeat LFTs at 1 month and 6 months

Investigation of Abnormal LFTs - Raised ALT / AST

If still abnormal at 6 months: Consider referral to secondary care Hepatitis serology (B, C) Iron studies transferrin saturation + ferritin Autoantibodies & immunoglobulins Consider caeruloplasmin Alpha-1- antitrypsin Coeliac serology TFTs, lipids/glucose Consider liver biopsy esp if ALT > 100)

What is the Value of Liver Biopsy in Abnormal LFTs?

The most accurate way to grade the severity of liver disease Aminotransferase levels correlate poorly with histological activity Narrows the diagnostic options, if not diagnostic

Abnormal LFTs - Conclusions

Many abnormal LFTs will return to normal spontaneously An important minority of patients with abnormal LFTs will have important diagnoses, including communicable and potentially life threatening diseases Investigation requires clinical assessment and should be timely and pragmatic

GUIDELINES TO IX AND BX OF PATIENTS WITH ABNORMAL LFTs AND NO CLEAR DIAGNOSIS AFTER ROUTINE TESTS: WITH EMPHASIS ON FATTY LIVER AND NASH AS UNDERLYING DIAGNOSIS
SCREEN FOR XS ALCOHOL CONSUMPTION INTERVENE AND REVIEW

SCREEN FOR OCT/PD/RD DRUGS

SEROLOGICAL INVESTIGATIONS* NEGATIVE USS NO SPECIFIC DIAGNOSIS NO CLEAR CLINICAL (e.g. FHx A1 disease/xanthelasma/Signs CLD) ASSOCIATIONS WITH LIVER DISEASE

INTERVENE AND REVIEW

ABNORMAL CLINICAL SIGNS PRESENT

RE-EVALUATE DIAGNOSIS AND BIOPSY

NO CLINICAL SIGNS PERSISTENT ABNORMAL LFTs > 6/12

MEASURE: TG Chol. AST/ALT Ratio TFTs BP Fasting Blood Sugar Calculate BM1

NO CLINICAL SIGNS ALT >3x normal High risk LFT profile

IF ABNORMAL TREAT

CONFIRM TREATMENT EFFECTIVE

LIFESTYLE MODIFICATION MONITOR EFFECTIVENESS

LFTs NOT IMPROVED

LFTs IMPROVED RE-EVALUATE CLINICAL RISK FACTORS CONSIDER BIOPSY AND FURTHER IMAGING SEE GUIDANCE NOTES

LFTs WORSEN OR BECOME ABNORMAL

RETURN TO NORMAL OR IMPROVE

MONITOR

GUIDANCE NOTES
PREDICTIVE OF PATHOLOGY VS NORMAL: ALT > 2 x Normal AST: ALT >1 Age > 50 Low Platelet Count PREDICTORS OF NASH AND FIBROSIS IN PRESENCE OF NASH ALT > 2 x Normal AST > ALT Moderate Central Obesity BM1 > 28 NIDDM/Impaired GTT BP TGs. OTHER GROUPS WITH HIGH RISK PATHOLOGY: Raised Conjugated Bili with: ALT ALK P Consider: BX; MRCP; ERCP Any abnormality of ALK P in addition to abnormality ALT/AST Consider BX

SUGGESTED ROUTINE SEROLOGICAL INVESTIGATIONS: Alpha 1 AT; HAV; HBV; HCV; AIP and Igs; Fe Studies and HFE genotype; Caeruloplasmin; USS Fatty Change or Normal echo only; Bilirubin and haemolysis studies if appropriate - ANY ABNORMALITIES IN THESE PARAMETERS, RE-EVALUATE POTENTIAL DIAGNOSIS AND CONSIDER BIOPSY
N.B. THESE NOTES/ALGORITHMS ARE FOR GUIDANCE ONLY. THIS IS A MOVING FIELD AND DESPITE IMPROVEMENTS IN SEROLOGICAL AND RADIOLOGICAL TECHNIQUES, THERE REMAIN SMALL NUMBERS OF PATIENTS WHO HAVE SIGNIFICANT LIVER DISEASE WITH ONLY MILDLY ABNORMAL LFTs. THE ALGORITHM IS NO SUBSTITUTE FOR CAREFUL AND REPEATED CLINICAL EVALUATION AND CLINICAL VIGILANCE.

THANK YOU