themed week 7 - liver

7/26/2019 Themed Week 7 - LIVER

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THEMED WEEK 7: LIVER

Hepatitis – inflammation of the liver1. Acute

<6 months, usually <3months

Ranges from mild self-limiting illness to fulminant liver failure

2. Chronic

Ongoing hepatitis > 6 months

Chronic hepatitis can cause fibrosis leading to cirrhosis

3. Liver enzymes in hepatitis

a. Usually ^ ALT/AST – the “transaminases” indicate liver cell (hepatocellular) damage

Blood tests1. Hepatitis serology:

Hep A IgM- acute infection, IgG – past infection

Hep B sAg, eAg, sAb, cAb IgM and IgG, eAb, HBV DNA

HCV antibodies and RNA PCR

Delta Ab and Delta RNA (only on a background of HBV)

HEV IgM and IgG, HEV RNA

2. Autoantibodies

Antinuclear antibody (ANA) and anti-smooth muscle antibody (ASMA) in autoimmune

hepatitis (AIH)

Anti-mitochondrial antibody (AMA) in Primary Biliary Cirrhosis (PBC)

3. Immunoglobulins

↑ IgG – autoimmune hepatitis

↑ IgM – PBC

↑ IgA – alcoholic liver disease

4. Iron and copper studies

Hemochromatosis: ↑ ferritin and transferrin saturation

Wilson’s disease: LOW caeruloplasmin and ↑ urinary copper

One in red should be

done as initial tests in

a patient with acute

hepatitis!!




Virus Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E

Type of virus ssRNApartially

dsDNAssRNA

Circular defective

ssRNAssRNA

Viral family

Hepatovirus;

related topicornavirus

Hepadnavirus Flaviridae

Subviral particle

in Deltaviridaefamily

Calicivirus

Route of

transmission

Fecal-oral

(contaminated

food or water)

Parenteral,

sexual

contact,

perinatal

Parenteral;

intranasal cocaine

use is a risk factor

Parenteral Fecal-oral

incubation

period2–4 weeks 1–4 months 7–8 weeks Same as HBV 4–5 weeks

Frequency of

chronic liver

disease

Never 10% ∼80%

5% (coinfection);

≤70% for

superinfection

Never

Diagnosis

Detection of

serum IgM

antibodies

Detection of

HBsAg or

antibody to

HBcAg

PCR for HCVRNA; 3rd-

generation ELISA

for antibody

detection

Detection of IgMand IgG

antibodies; HDV

RNA serum;

HDAg in liver

PCR for HEVRNA; detection

of serum IgM

and IgG

antibodies

Case of HAV 40 year old University lecturer invited to give talk at International meeting in Bangladesh

Attended travel clinic a few months prior to trip; found to be HAV IgG negative so vaccination

recommended

5 weeks after returning felt unwell with:

→ anorexia, nausea, abdominal discomfort,

then she noticed:

→ dark urine, pale stools

→ jaundice

o/e: pyrexial, tender slightly enlarged liver

Investigations:

→ Bilirubin 80 iu/l (ULN=19),

→ Alkaline phosphatase, ALP (bile stasis) 200 iu/l (ULN=120)

→ Alanine transaminase, ALT (liver cell inf, inj, death) 2,430 iu/ l (ULN=45)

→ International normalised ratio (INR) 1.8

→ HBsAg negative, HCV Ab negative, HAV IgM negative [but IgG positive following vaccination]

→ HEV IgM requested

Treatment:

→ No specific therapy is available. Avoid alcohol

→ Importance of good personal hygiene emphasised

Progress:

→ Repeat LFTs in 5 days:

→ Bil↓ 55, ALT↓ 1420, INR↓ 1.3

→ Felt better in herself over next week and confirmed HEV IgM positive (can also request HEV

RNA)

→ Repeat LFTs in 6 weeks: Bil – normal, ALT 90, INR 1.0

Summary:

→ Self-limiting infection, followed by recovery, but overall population mortality rates of 0.5%- 4%

NB: mortality rate of 20% among pregnant women in 3rd

trimester




Hepatitis E1. HEV : 4 major genotypes – genotypes 1 & 2 are restricted to humans and transmitted by

contaminated water in developing countries

2. Genotypes 3 & 4 infect humans, pigs and other mammalian species;

3. G3 is largely responsible for indigenous cases of HEV in Europe, N America & Australia4. Acute hepatitis E increasingly seen in developed countries

5. Genotype – 3, HEV is now the most common acute viral hepatitis in the UK

6. Zoonoses found in pigs - 85% of pigs affected

7. Undercooked meat implicated, can be transmitted by transfusion also

8. High mortality in patients with chronic liver disease

9. Please test for HEV in patients with acute hepatitis or decompensated cirrhosis

Hepatitis B1. Risk factors

a. Sexual - sex workers and homosexuals are particular at risk.b. Parenteral - IVDA, Health Workers are at increased risk.

c. Perinatal - Mothers who are HBeAg positive are much more likely to transmit to their

offspring than those who are not. Perinatal transmission is the main means of transmission in

high prevalence populations.

Marker* Interpretation

HBsAg Exposure to Hepatitis B virus. Present in acute or chronic infection

Anti-HBs antibody Immunity acquired via natural infection or immunisation

HBeAg Marker of infectivity. It correlates with high level of viral replication

Anti-HBe antibody It correlates with low level of viral replication

Anti-HBc IgM antibody Infection in previous 6 months

Anti-HBc IgG antibody Distant HBV infection or chronic HBV infection. Past or chronic HBV

Hep B DNA >105 copies /mL Rapid viral replication. Indicates active replication of virus, more accurate

than HBeAg especially in cases of escape mutants. Used mainly for

monitoring response to therapy.

2. Safe and effective vaccines against HBV have been available since 1982 – over 1 billion doses have

been used world wide

3. HB vaccine is 95% effective in preventing chronic infections from developing

4. HB vaccine is the first vaccine against a major human cancer

5. Individuals with chronic HBV are at high risk of death from cirrhosis and liver cancer.

6. Surveillance for hepatocellular cancer is recommended in cirrhotics using 6 monthly ultrasound and

α-fetoprotein




CASE OF HEB 1• 28 year old attends GU clinic

• Offered screening for sexually transmitted diseases

• Found to be HBsAg postive

• Subsequent tests show:

→ HBeAg positive, HBV DNA positive

→ LFTs normal except ALT of 96 iu/l

→ Abdo ultrasound scan - normal

→ Liver biopsy - moderate chronic hepatitis

CASE OF HEB 2• 57 year old man presents with fatigue, RUQ discomfort and weight loss

• Social history – born in Hong Kong, came to UK 30 years ago, owns

Chinese restaurant

• o/e; Palmar erythema, Firm palpable liver edge, Spleen palpable

• Investigations:

→

Bil 19 iu/l, Alkaline phosphatase 115 iu/l,→ ALT 72 iu/l, AST 80 iu/l, Albumin 32 iu/l (LOW).

→ Prothrombin time – 2 seconds prolonged

→ HBsAg positive, HBeAb positive, HBV DNA positive

→ U/S scan – liver has irregular margin and spleen is enlarged

consistent with portal hypertension

Management:

Undertake surveillance for

complications of cirrhosis

such as oesophageal varices

and hepatocellular cancer

Specific anti-viral therapy -Lower viral load with agents

such as Lamivudine +

Tenofovir

Hepatitis C1. Virology

a. Daily virion production >1012

virions/day

b. RNA-dependent RNA polymerase

c. Frequent mutations and no ‘proof reading’

d. Results in HCV variants (quasispecies)

2. Six major types

3. Causes chronic liver disease and HCC

4. Transmission

a. Unsafe injection practice/contaminated needles

b. Blood or blood products (not since 1991 when screening was introduced)

c. Rarely by sexual exposure

d. Very rarely during medical care.

5. Indications for screening for HCV

a. Any hx of injecting or intranasal drug useb. Blood transfusion or solid organ transplant before 1992(UK)

c. Blood product for clotting problem produced before 1987

d. Long term dialysis

e. Any elevation of ALT

f. HIV infection

6. Current treatment

Genotype 2-6

Pegylated interferon Alpha 2a (PEGASYS) + Ribavirin

Pegylated interferon Alpha 2b (Pegintron)– 1.5 mcg/kg + Ribavirin

Genotype 1 Pegylated interferon Alpha 2a or 2b + ribavirin




+/- protease inhibitor Telaprevir or Boceprevir

7. Progression

CASE OF HCV• 28 year single man in drug rehab – on

maintenance methadone 90mls/day.

• First use of illegal drugs age 16 yrs, moved on to

injecting drug use aged 18 yrs

• Offered screening for blood borne viruses in

prison when on remand for drug-related crime

Investigations:

HBsAg negative, HBcAb and HBsAb negative

HIV negative

HCV Ab positive

Management:

HB vaccine – accelerated course

Advice on harm reduction measures Check:

→ HCV RNA - positive,

→ HCV genotype – 3

→ LFTs – ALT 103

→ Refer for further assessment and treatment

→ Liver ultrasound scan - mild fatty/fibrotic

change

• Declined liver biopsy – keen to proceed to

treatment

• Discussed all the side-effects of pegylated

interferon alpha and ribavirin• Completed 24 weeks combination therapy

despite developing depression (needed anti-

depressant), weight loss and anaemia (needed

dose reduction of Ribavirin)

• HCV RNA 6 months later = negative (Sustained

Virological Response)




Introduction to autoimmune liver disease1. It is a chronic inflammatory liver diseases

2. RARE (approx 5% of liver disease)

3. It is important because;

a. Involved YOUNG patients

b. Treatable

c. Symptoms

4. Mild liver disease -> CIRRHOSIS

Figure 1 Characteristic histological and radiological features of autoimmune liver diseases




Diagnosis and management of

Primary Biliary Cirrhosis (PBC) = AMA + ↑ALP1. Predominantly FEMALE 10:1

2. Middle aged women

3. Damage to small intrahepatic bile ducts

4. Genetic susceptibility + trigger (infectious, environmental toxins, hormones)

Symptoms1. Asymptomatic (Incidental finding – 70-

80%)

2. Fatigue

3. Itch

4. Dry eyes and dry mouth

5. Poor memory

6. Symptoms of advanced liver disease

Diagnostic criteria1. Abnormal LFTs (cholestatic - bile cannot

flow from the liver to the duodenum)

2.

Positive Anti-mitochondrial Antibody

(AMA)

3. Compatible histology

4. 2 of above = probable PBC

5. 3 of above = definite PBC6. Liver biopsy, usually not required unless:

a. Uncertain diagnosis

b. Possibility of overlap syndrome

Disease aetiology Genetic associations – allele association studies have shown IL12 regulation

and pathway, various other cytokines and the HLA region to be important

Association with Novosphingobium aromaticivorans first reported in 2003

and confirmed by others including in a mouse model

Associated with coeliac disease – possibly via alteration of gut permeability

or immune regulation of exposure to gut luminal allergens

Treatment aim

Disease Progression

Ursodeoxycholic Acid (UDCA)

Hydrophilic bile acid

SE: weight gain, hair thinning and diarrhoea

Transplantation – guided by Mayo score

Definitive treatment, only one that improves prognosis

10% of all transplants done for PBC – up to 70 years old

Very good outcome – normal survival in the 90% who survive the first year

Symptoms relieved

Itch – Cholestyramine (Rifampicin Naltrexone, Sertraline)

Fatigue - No treatment with strong evidence – some suggest modafinil but many side effects

Review contributing factors

Anaemia

Thyroid disease

Autonomic dysfunction

Obstructive sleep apnoea




Complications

Varices – screen and treat – primary prophylaxis with propanolol (s.e.=tiredness)

Osteoporosis – oral high dose Vit D and calcium. Monitor Vit D (not absorbed in severe cholestasis)

so may need parenteral

Monitor for evidence of cirrhosis – US and bloods

HCC – annual USS and AFP

Case presentation 54 year old lady

Presents to GP with tiredness for many

years

Sleeps through the day

Always worn out

After a busy day it takes her several days to

recover

Itching which keeps her awake at night

PMHx High cholesterol

Depression (diagnosed when originally

presented with tiredness)

Medication Citalopram

Social history Non smoker

Alcohol 5 units / week

Works as a teacher

Examination and Ix

Examination – xanthelasma and scratch

marks on arms and legs

Bloods

→ U&Es normal

→ FBC normal

LFTs –

→ Bilirubin 12 (0 - 21)

→ ALP 364 (30 - 130)

→ ALT 46 (0 – 40)

→ Albumin 42 (35 – 50)

TFTs normal

Autoantibodies

→ Anti-Nuclear Antibody Negative

→ Anti-Mitochondrial Ab Positive 1:640

→ Anti-smooth Muscle Antibody Negative

Immunoglobulins

→ IgA 1.4 (0.64 – 2.97)

→ IgG 12.5 (5.8 – 15.4)

→ IgM 5.42 (0.24 – 1.9)

Liver screen→ Viral hepatitis – Negative HBV sAG, HCV

antibodies

→ Ferritin – Normal

→ Alpha-feto protein 3

→ Coeliac antibodies

→ NB we don‟t always check caeruloplasmin

and alpha-1 anti-trypsin

→ Abdo US - Normal

Autoimmune Hepatitis (AIH) - ANA / ASMA + raised IgG

1. Immune attack on hepatocytes2. Any age

3. Female : Male 3:1

4. Can be precipitated by drugs; imatinib

5. Genetic susceptibility (HLA associations) + trigger – drug or infection - Brucella, tetracyclines, herpes 6

viruses, HCV, parvovirus, post-partum




Type 1 75% cases

All ages

F:M 3:1

ANA / ASMA

Type 2 <10% cases

Young adults

F: M 10:1

Commoner in Southern Europe

Anti-liver kidney microsomal-1 (LKM-1) antibodies or anti-liver

cytosolic antibodies (LC-1)

Presentation Often asymptomatic (incidental finding)

Symptomatic

Fatigue, anorexia, nausea, joint pains

Acute hepatitis

Complications of cirrhosis

Investigations

Exclude drug, viral and metabolic causes(full liver screen)

Combination of hepatitic LFTs,

autoantibodies and immunoglobulins

Usually need liver biopsy

→ Confirm diagnosis & stage

Treatment Immunosuppression

→ Steroids

→ Azathioprine

→ MMF, Tacrolimus

Transplantation – rarely unless cirrhotic at

presentation

Aim for normalisation of ALT and IgG or

BIOPSY Duration of therapy uncertain. c.50% of

cases do not relapse when treatment

stopped at 2 years.

Case presentation 28 year old female

Presented to GP with several month history of:

→ Joint aches and pains

→ Anorexia and nausea No medications

No risk factors for viral hepatitis

Strong FHx of A/I disease (coeliac disease, RA

and thyroid disease)

Examination Not jaundice

Not encephalopathic

No stigmata of CLD

Bloods FBC – Normal

U&Es – Normal

LFTS

→ Bilirubin 32 (0 – 30)

→

ALT 864 (0 – 40)→ ALP 124 (30 – 130)

→ Albumin 40 (35 – 50)

Coagulation screen – Normal

Autoantibodies ANA 1:320

AMA Negative

ASMA 1:160

Immunoglobulins

IgA 1.8 (0.64 – 2.97) IgG 22.4 (5.8 – 15.4)

IgM 1.2 (0.24 – 1.9)

Viral hepatitis screen - Negative

Ferritin, caeruloplasmin and α1AT – Negative

US - Normal




Primary Sclerosing Cholangitis (PSC) – ANCA + ↑ALP Inflammation and fibrosis of intra and extra-hepatic bile ducts

Multifocal bile duct strictures

Small duct PSC – clinical, biochemical and histological features of PSC but normal cholangiogram

60-80% patients with PSC have IBD

Presentation Often asymptomatic

o Incidental finding of abnormal LFTs

Symptomatic

o Fatigue, itch, RUQ pain, weight loss

o Cholangitis (often not at presentation)

o Jaundice and complications of cirrhosis

Investigations Bloods - Cholestasis

US – often normal

CT – often not helpful in diagnosis

Magnetic resonance cholangiopancreatography (MRCP) – gold standard

o multi-focal, short, annular strictures alternating with normal or dilated segments „beading‟

Liver biopsy

o Early stages – often non-specific

o „onion skin‟ fibrosis (periductal concentric)

ERCP – not usually used for diagnosis only if there is diagnostic doubt

Management1. Look for IBD

2. Strictures

a. If dominant and causing symptoms (cholangitis, jaundice, pruritis, worsening LFTs) – TREAT

i. ERCP (sphincterotomy, balloon dilatation, stent)

ii. Surgical (bypass of biliary stricture)

3. Itch (manage as for PBC)

4. Bone disease

5. Screen for malignancy

a. cholangiocarcinoma

b. colorectal6. Transplantation




Case presentation 46 year old man

Incidental finding of abnormal LFTs

10 year history of Ulcerative Colitis

DHx - Mesalazine

Social Hx - No alcohol, Non smoker

Investigations FBC – Normal

U&Es – Normal

LFTs

→ Bilirubin 28 (0 – 30)

→ ALP 420 (30 – 130)

→ ALT 42 (0 – 40)

→ Albumin 40 (35 – 50)

Autoantibodies

→ ANA, AMA, ASMA – Negative

→ ANCA – 1:360

Immunoglobulins - Normal

US – Normal

MRCP→ Multifocal strictures and segmental

dilatations

→ Involvement of intra and extra hepatic ducts

→ Beading

→ No mass lesion

SummaryPBC AIH PSC

Middle aged women

↑ALP + AMA + IgM

Symptoms of fatigue, itch,

dry eyes and dry mouth

Treat with UDCA

↑ALT + ANA + ASMA

Any age, any sex

Often asymptomatic

Treat with

immunosuppression

↑ALP + ANCA

Men

Associated with IBD

Screen for cholangiocarcinoma and

bowel cancer

AMA → PRIMARY BILIARY CIRRHOSIS

ANA/ASMA → AUTOIMMUNE HEPATITIS

ANCA → PSC

IGA → ALCOHOL, NAFLD

IGM → PRIMARY BILIARY CIRRHOSIS

IGG → AUTOIMMUNE HEPATITIS




Classification1. Primary liver cancer

a. Cancers that originate in the liver

i. Hepatocellular carcinomas

ii. Cholangiocarcinomas

2. Secondary

a. Cancers that spread to the liver from an extra-hepatic primary site

b. Metastatic

Primary liver cancer

Epidemiology

1. 5th

most common malignancy worldwide

2. 3rd

most frequent cause of cancer mortality

3. Prevalent in areas of Asia and Africa

4. 4x more common in men vs. women

Aetiology 90% of patients with hepatocellular carcinoma are (+) for HBV

HCC development is related to integration of viral HBV to the genome of the host

More common in developing

country: higher incidence of

Hep B and C




Risk factors chronic, low grade liver cell damage and mitosis ->increased risk of HCC

alcoholic liver disease,

alpha 1-anti trypsin deficiency,

hemochromatosis,

tyrosinemia,

primary biliary cirrhosis,

cirrhosis

associated NASH

Clinical presentation1. asymptomatic – underlying cirrhosis

2. abdominal pain with a RUQ mass

3. a friction rub/bruit

4. Blood tinged ascites (20%)

5. jaundice

6. Small percentage may have a paraneoplastic syndrome

a. Erythrocytosis

b. Hypercalcemia

c. Diarrhea

Investigations1. FBC

a. Anemia, thrombocytopenia

2. Bleeding parameters

a. Prolonged PT/INR

3. Liver function test

a. Elevated liver enzymes

b. Increased bilirubin levels

4. Serum electrolytes

a. Hyponatremia (LOW Na+)5. High AFP levels (>500 ug/L) seen in 70-80%

6. High AFP + adult with liver disease + no obvious GIT

tumor strongly suggest HCC

7. Correlation between history, PE, diagnostic

examinations

8. Tissue diagnosis is not required – percutaneous liver biopsy of the tumour is discouraged 2‟ to

concern for seeding the biopsy track.

9. CT scan and MRI are preferred modalities for diagnosis of HCC

10. Ultrasound – initial test if HCC is suspected

11. Hepatic artery angiography




Management1. Surgical resection – gold standard

a. generally offered to patients with liver-localized disease & adequate hepatic reserve for

recovery

b. Important to determine hepatic reserve

c. Cause of death after resection liver failure

2. Liver transplantation

a. offered to cirrhotic patients with no major cardiopulmonary comorbid conditions

b. local disease is limited

3. Thermal ablation

a. Killing small tumors via RF ablation

b. Can be used for:

i. Poor candidates for surgical resection

ii. Inaccessible tumors

iii. Large tumor burden

iv. Decreased hepatic reserve

4. Embolization

a. Targets the tumor by cutting of the blood supply

b. Ex: transarterial chemoembolization (TACE), transarterial embolization (TAE), and

radioembolization

c. Can be used to “down stage” a tumor or as a “bridge” for patients awaiting transplant




Secondary liver cancer1. Most common tumor of the liver

2. 20x more common than primary liver cancer

3. Most common primary tumors include the GIT, lung, breast

& melanomas.4. Less common: thyroid, prostate, and skin

Pathogenesis Vulnerable to invasion by tumor because of

→ Its size

→ high rate of blood flow

→ double perfusion by the hepatic artery and portal

vein

Next most common site of metastases after the lymph

nodes

Clinical presentation Most patients with metastases present with symptoms referable to the primary tumor

Nonspecific symptoms of weakness, weight loss, fever, sweating, and loss of appetite

Investigation

Blood exams increase in serum alkaline phosphatase is the most

common and frequently the only abnormality

Hypoalbuminemia, anemia, and mild elevation of

aminotransferase

Substantially elevated serum levels of CEA

Imaging Ultrasound

CT scan

MRI

Treatment For colonic carcinomas:

→ Out of 15% of patients with metastases limited to the liver, 20% are potentially resectable forcure

Management is mostly palliative

Most respond poorly to all forms of treatment

Systemic chemotherapy may slow tumor growth and reduce symptoms, but it does not alter the

prognosis

Chemoembolization, intrahepatic chemotherapy, and alcohol or radiofrequency ablation may provide

palliation




ACUTE LIVER FAILURE Liver failure occurring within 26 weeks of

onset of symptoms

Fulminant – within 8 weeks

Hyperacute – within 1 week

Prognosis: age (worse in very young and

very old), cause (worse in drugs and non-

ABCDE), acuteness (more acute the

better)

Potential mechanisms of interactionand toxicity

Inadequate supply of the conjugate

Induction of one (toxic) pathway over a

safer route

Inhibition of the safer metabolic route

Competition at the enzyme with an

alternative substrate

What the liver does Immune organ

Liver is central to immune function –

function in clearing bacteraemia from gut,

opsonisation, kuppfer cells etc

Ergo, in acute (and chronic) liver failure

bacterial (80%) and fungal (30%)

infections are common and frequently

contribute to death

Role in refulation of vascular system Mechanism not completely clear but

mainly mediated through nitrous oxide

Vasodilation (Systemic Iinflammatory

Response Syndrome)

Cerebral autoregulation

Hepatorenal syndrome

Control of metabolic status In severe ALF, lactic acidosis occurs

(circulatory failure)

Before this metabolic alkalosis may occur

Abnormal water retention -

hyponatraemia, hypokalaemia, etc etc

SummaryPatients develop:

cerebral dysfunction then cerebral oedema

Coagulopathy

severe refractory hypoglycaemia

sepsis

renal failure and circulatory failure

electrolyte abnormalities




CASE 1

Presentation A 30 year old farmer is brought to A

and E by his family

They report that he has been actingoddly for 3 months. He has stopped

eating and has been drinking alcohol

daily.

In the last 3 days they suspect he took

some tablets and he has become

confused and drowsy

BLOODS/PHYSIOLOGY ALT 25,000 (0-40), Bilirubin 200 (0-21)

Prothrombin time 40 secs (n<14)

Creatinine 250

BP 85/50, pulse 120, warm peripheries

Bleeds when cannula inserted

Fulfils definition of hyperacute liver

failure – coagulaopathy, cerebral

dysfunction with hepatic dysfunction

within 7 days of illness

Management ABC! – fluids and lots

Airway management – would be intubated in UK if

drowsy Check blood glucose and prophylatically give 20%

glucose

Sepsis – cultures, low threshold for broad spectrum

antibiotics

Replace glutathione with N-acetylcysteine (NAC)

Treatment Supportive plus glutathione replacement – NAC given

until PT improves.

Resus and support organ failure

Liver transplant if any of the following:

→ Persisting acidosis after fluids (pH<7.3)

→ PT>100 and creatinine >300

→ Grade 3 or 4 encephalopathy

Plus „suitable‟ – EARLY TRANSFER

70-80% die if transplant criteria are fulfilled

With transplant, >50% survival

c.100-20 deaths a year in UK, 20 transplants

Many saved with NAC and supportive therapy

If they recover without transplant, liver returns to

normal

Death usually occurs on day 4 or 5 if it is going to

happen – so transplant is very urgent.

Paracetamol metabolism

Therapeutic Dose Overdose

It is mostly converted to nontoxic metabolites

via Phase II metabolism by conjugation with

sulfate and glucuronide, with a small portion

being oxidized via the CYP450 enzyme system.

Cytochromes P450 2E1 and 3A4 convert

approximately 5% of paracetamol to a highly

reactive intermediary metabolite, N-acetyl-p-

benzoquinoneimine (NAPQI)

Under normal conditions, NAPQI is detoxified by

conjugation with glutathione to form cysteine

and mercapturic acid conjugates.

The sulfate and glucuronide pathways become

saturated, and more paracetamol is shunted to

the CYP450 system to produce NAPQI.

As a result, hepatocellular supplies of

glutathione become depleted, as the demand

for glutathione is higher than its regeneration.

NAPQI therefore remains in its toxic form in the

liver and reacts with cellular membrane

molecules, resulting in widespread hepatocyte

damage and death, leading to acute hepatic

necrosis – especially in zone 3 of the liver

So, anything that increases the conjugation pathway via CYP450 induction is more likely to lead

to toxicity, especially if the possibility of detoxification by glutathione is reduced

So, (1) starvation/nutritional status, being (2) underweight and taking (3) enzyme inducers (alcohol

and phenytoin), make toxicity more likely.

ALF can occur at therapeutic doses in high risk individuals

http://en.wikipedia.org/wiki/Drug_metabolism

http://en.wikipedia.org/wiki/Sulfate

http://en.wikipedia.org/wiki/Cytochrome_P450_oxidase

http://en.wikipedia.org/wiki/NAPQI



http://en.wikipedia.org/wiki/Glutathione

http://en.wikipedia.org/wiki/Cell_membrane

http://en.wikipedia.org/wiki/Cell_membrane

http://en.wikipedia.org/wiki/Glutathione




http://en.wikipedia.org/wiki/Cytochrome_P450_oxidase

http://en.wikipedia.org/wiki/Sulfate






CASE 2 55 year old woman presents to primary care

Unwell for 3 weeks with non-specific N and V,

lethargy, dark urine

GP notes abnormal LFTs – ALT 800, bilirubin 30,

albumin 25, PT 16 secs. Cause unclear – checks a „liver screen‟, „watchful

waiting‟

2 weeks later, husband brings her to A and E

because she is confused

Drug and risk history – only medication is

traditional medicine. Nothing else for >3/12

No risks for parenteral transmission

No FH. Does not drink, no PMH.

HBV/HCV/HAV and auto-antibodies negative

PT now 25, bilirubin 150

Does she have ALF? If so, is it severe?

ALF - yes – cerebral disturbance with

coagulopathy within 8 weeks of onset

Severity criteria for transplant:→ Prothrombin time > 100 seconds

OR

Three of the following:

→ Age < 10 yr or > 40 years

→ Cause: Hep C or E (or non-ABCDE)

→ Drug reaction

→ Jaundice > 7 days before onset of

encephelopathy

→ PT>50

→ Bilirubin >300

Currently transplant criteria not met

Supportive care

Likely induced by traditional medicine (many

examples)

Need close monitoring as may well continue to

deteriorate




CIRRHOSISCirrhosis, as the end stage of chronic liver disease, is defined by three main

morphologic characteristics:

a. Bridging fibrous septa

b. Diffuse disruption of the architecture of the entire liver.

c. Regenerative parenchymal nodules

Pathogenesis1. The central pathogenic processes in cirrhosis are

a. Death of hepatocytes,

b. Extracellular matrix (ECM) deposition, and

c. Vascular reorganization.

2. Excess of Types I and III collagen are deposited in the space of Disse, creating fibrotic septal tracts.

3. The vascular architecture of the liver is disrupted by the parenchymal damage and scarring, with the

formation of new vascular channels in the fibrotic septa.

4. Activated hepatic stellate cells, portal fibroblasts, and myofibroblasts of bone marrow origin have

been identified as major collagen-producing cells in the injured liver.

5. These cells are activated by fibrogenic cytokines such as TGF-β1, angiotensin II, and leptin.

Clinical features 40% - cirrhosis are asymptomatic until late in the course of the disease.




Symptomatic - nonspecific C/F : anorexia, weight loss, weakness…

Diagnosis Clinical examination – spider naevi, leuconychia, palmer erythema, gynaecomastia, Splenomegaly,

Testicular atrophy. Palmar contractures

Abnormal LFT‟s – low albumin. Ultrasound – heterogeneous liver, enlarged spleen

Low white cells and platelets.

Signs of decompensation Increasing jaundice

Increasing ascites

→ Abdominal pain

→ Abdominal distension

→ Breathlessness

→ Peripheral Oedema

Confusion – flap

Internal bleeding

Complications of cirrhosis

1. Liver cell failurea. Jaundice: Bilirubin 223 (<17)

b. Albumin 23g/l (>40)

c. Prothrombin time 23 secs (11-13)

2. Ascitesa. Portal Hypertension

b. Abdominal distension with shifting dullness

c. Transudate – albumin 9g/l

d. Ascitic WBC – 140/l (<500); 98% mononuclear cells.

e. Prognosis – 50% die within 2 years of onset

PARACENTESIS 14 litre paracentesis – protein replacement with 7x 100ml 20% albumin

Spironolactone and furosemide prophylaxis

Speeds recovery

Shortens hospital admission Total volume paracentesis safe with colloid replacement

Lowers variceal pressure gradient

Decreases variceal size

→ Refractory ascites: (prognosis)

o 50% die <6 months

o 75% die <1 year




3. Hepatorenal syndromea. May be precipitated by: (1) Over diuresis, (2) Infections

b. The syndrome is heralded by a drop in urine output and rising blood urea nitrogen and creatinine

values

c. If unresponsive to diuretic withdrawal and colloid infusion:

i. Almost universally fatal.

ii. Dialysis resistant but may respond to vasoconstriction with Terlipressin (counteract

splanchnic vasodilation)

4. Variceal bleedinga. Normal portal venous pressure <7mmHg.

b. Varices develop when portal pressure rises >10mmHg.

c. In portal hypertension collaterals develop Portal-Systemic Shunting

d. Many patients with Cirrhosis present with:

i. Haematemesis

ii. Malaenaiii. Anaemia

e. Gastroscopy shows

i. Oesophageal Varices

ii. Portal Gastropathy

Prediction of first variceal bleed1. Endoscopic findings:

a. Size of varices

b. Red wall markings (predict bleeding time)

2. Severity of liver disease

3. Intra variceal (portal) pressure

Haemodynamic Factors in Pathophysiology of Portal Hypertension1. Increase in splanchnic (and systemic) blood flow

- splanchnic arteriolar vasodilatation

- Increased cardiac output

- Decrease splanchnic and systemic vascular resistance

- Treatment: Vasoconstrictor drugs eg. Vasopressin analogues, Beta-2-adrenoreceptors

2. Increase in intra hepatic resistance

- structural alteration

- active contraction of sinusoidal myofibroblasts- Treatment: Vasodilatory drugs eg. nitrates, alpha blockers, Calcium channel blockers.

Emergency1. Baloon tamponade

2. Vasoconstrictors: Vasopressin and Terlipressin

3. Somatostatin: decreases portal pressure and azygos blood flow

4. Emergency Sclerotherapy / Rubber Band Ligation

5. Encephalopathya. A spectrum of neuropsychiatric abnormalities observed in patients with hepatic dysfunction.

b. Vienna Classification 2002i. Type A - Acute liver failure associated




ii. Type B - HE in patients with porto-systemic Bypass and no liver disease

iii. Type C - HE in chronic liver disease/ Cirrhosis

Treatment1. Treat precipitant – infection, overdiuresis, bleeding

2. Maintain dietary protein intake / nutrition

3. Non absorbable disaccharide's

a. lactulose

b. lactitol

4. Non absorbable Antibiotics

a. Neomycin

b. Metronidazole

5. Hepatocellular of cirrhosis

6. Hepatocellular Carcinomaa. Most commonly seen in:

a. Hepatitis C after 30 years

b. Hepatitis B

c. Alcoholic Cirrhosis

d. Haemachromatosis

b. Screen for with ultrasound and alpha fetoprotein

themed week 7 - liver

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