Prof. MUDr. Viera Kupčová, CSc.

H e p a t i c i n s u f f i c i e n c y Prof. MUDr. Viera Kupčová, CSc.

MEDICAL FACULTY COMENIUS UNIVERSITY BRATISLAVA

IIIrd. Dpt. of Internal Medicine Medical Faculty, Comenius University, Dérer’s Hospital, UNIVERSITY HOSPITAL BRATISLAVA

possibilities:

- syndrom caused by serious hepatic function impairment -›- progressive disturbance of the homeostasis of organism -› - following death - with edema of brain or multiorgan failure -› - need of fast restitution - or liver function substitution is in order

- if 80-90% decrease in capacity of liver function (necrosis, apoptosis) -›- development of liver failure (fulminant, acute or subacute liver failure)- or liver failure based on the chronic liver disease (ACLF)

(acute-on-chronic liver failure) acute failure based on the chronic liver disease

- sometimes it may be a functional defect of liver cell without parenchyme deficit- (Reys syndrome, acute steatosis in gravidity, TTC toxicity)

Pathophysiology of liver failure I.

- Acute disease- rapid reaching of critical liver function limitation (days-weeks) for the failure development

- Chronic disease- (development takes years) -› plus unexpected acute complication -- e.g. GIT bleeding, severe infection (spontaneous bacterial peritonitis,

bronchopneumonia, infection of urogenital tract etc.), electrolyte dysbalance, surgery, injury, alcohol, etc.)

- possible displacement outside of the critical limit -› liver failure

- Compensated hepatic insufficiency:- if a reduction in liver function to a critical level is not present

-3 basic pathophysiological actions (in both acute and chronic processes)

- liver (hepatocellular) failure- inflammation- portal hypertension

Pathophysiology of liver failure II.

- Clinical indicators of hepatic insufficiency:- icterus, spider nevi, palmar erythema, hepatic foetor, liver encephalopathy,

muscle and subcutis hypotrophy, decreased physical efficiency

- Laboratory indicators of hepatic insufficiency: - billirubine increase, albumin and coagulation factors decrease (II,V,VII,IX,X), INR,Quick

- Prognostic scoring systems: Child-Pugh, MELD score, etc.

Pathophysiology of liver failure III.

Classification of hepatic function - Child-Pugh Score

1 point 2 point 3 point

Albumin (g/l) > 35 35-28 < 28

Total bilirubin (µmol/l) < 34,2 34,2-51,3 > 51,3

PT prolongation (s) < 4 4-6 > 6

Ascites Absent Slight Moderate

Encephalopathy Absent Grade 1 or 2 Grade 3 or 4

Interpretation: Class A: 5-6 points, Class B: 7-9 points, Class C: 10-15 points

- icterus- decrease of blood protein synthesis (albumin, coagulation factors) - disorders of cholesterol, fat and glucose metabolism- impairement of inactivation of various splanchnic and systemic mediators

and hormones- impairment of detoxication and metabolic functions (subsequent

foetor hepaticus, encephalopathy, brain edema)- cholestasis (malabsorption of fats and fat-soluble vitamins, accumulation

of cholesterol and bile acids) may also be present

Hepatocellular failure - manifestations

- bilirubin accumulation- water-insoluble bilirubin -› transported bound to albumin -›- glucuronyltransferase -› conjugated to mono – or diglucuronide -› soluble -› - secreted by the active transport into the bile and by the bile into the duodenum- 15 % of the excreted bilirubin undergoes enterohepatic circulation

- in cholestasis - the conjugated form is predominant- in cholestasis there is also a disorder of bile acid secretion –› their accumulation -›

pruritus- in cholestasis - malabsorption of fat and fat-soluble vitamins are present

Icterus

- hypalbuminaemia, decreased albumin-globulin index- impaired intravascular volume regulation- swelling, serosal effusions (as a result of both hypalbuminaemia and

portal hypertension)- coagulopathy (due to a decrease in the synthesis of coagulation factors)- most pronounced manifestations in the external cascade of haemocoagulation

(Quick, INR)- complex impairment of haemostasis including anticoagulation factors and

factors of fibrinolysis is also possible- manifestations of disseminated intravascular coagulation (DIC) are also possible

Reduced cholesterol synthesis and impaired glucose metabolism

- decrease in serum cholesterol- impaired production of transport lipoproteins- increased insulin resistance, impaired glucose tolerance

Synthetic liver function impairment

- reduced inactivation of vasoactive substances of splanchnic origin – ›

development of portal hypertension syndrom- impaired metabolism and regulation of steroid effect- impotence, infertility- gynecomastia

Inflammation

- is related to the production of cytokines and their release into the circulation- almost every liver affection - accompanied by some degree of inflammation

in the liver tissue- in acute, massive liver parenchyma damage –› release of large amounts

of inflammatory cytokines from the liver into the blood circulation - in a massive active liver lesion –› release of TNF-alpha and interleukins –› fever- systemic inflammation, on the other hand, has an impact on both – hyperaemia

and liver function –› possible development of ACLF

Metabolism impairment of various mediators and hormones

- leads to terminal multiorgan failure in most patients with severe hepatic insufficiency- hyperaemia and venostasis in the splanchnic promote translocation of the

intestinal flora- hepatocellular insufficiency and systemic collateralization disable

the liver immunological filter- the most common sources of sepsis – spontaneous bacterial peritonitis (SBP),

urinary tract infections, pneumonia, bronchopneumonia, but also cannulation, catheters

Foetor hepaticus

- a sweet, light fecal odor in advanced hepatic insufficiency and liver failure- methylmercaptan and other substances of intestinal origin are not eliminated due

to the portosystemic collaterals, they are released from the lung circulation

into the alveolar and exhaled air

Immunodeficiency and sepsis

- change of blood flow parameters in portal bloodstream: reason:- increased resistance in liver microcirculation due to a disease process in the

liver parenchyma- increased activity of vasoactive substances in the systemic circulation - multiple causes:

- decreased clearance of vasoactive substances (hepatocellular insufficiencyand portosystemic collateralization)

- increased production (due to venostasis in the splanchnic bloodstream)- increased production of vasoactive cytokines due to inflammation in the liver- increased translocation of immunogenic substances of intestinal microflora into

portal blood

Circulatory disorders

Hepatic encephalopathy

- it usually represents an advanced hepatic impairment- in acute liver failure – type A- in chronic hepatic insufficiency – type B- in large portosystemic collateralization – type C- it generally represents a disorder of brain metabolism culminating in coma- decreased clearance of various substances of intenstinal origin by the liver

due to hepatocellular insufficiency as well as portosystemic collateralization(ammonia, mercaptans, some of fatty acids, etc. ), which by different mechanisms alter neurotransmitter metabolism and the internal brain milieu

- impaired metabolism some of amino acids in the brain and peripheral tissues- disorders of cerebral microcirculation (vasoactive mediators and intestinal cytokines

/in portal hypertension/ and hepatic /in inflammation/ origin)- 4 clinical stages of encephalopathy- typical symptoms: personality disorders, sleep disorders, memory disorders,

movement coordination disorders (constructional apraxia, asterixis - flapping tremor) in advanced stages general letargy and coma

- in differential diagnosis we need to distinguish delirium tremens, Wernicke encephalopathy, hepatolenticular degeneration in Wilson’s disease, latent psychose, etc.

Brain edema

- typically accompanied by acute liver failure- to a varying extent, it is combined with signs of hepatic encephalopathy- is a consequence of a complex brain circulation disorder, haematoencephalic

barrier permeability and osmotic conditions in brain tissue- increased levels of ammonia and its metabolic effects in the brain and increased

activity of inflammatory cytokines is important- ammonia stimulates anaerobic glycolysis and proteolysis- glutamine concentration increases (product of ammonia detoxification),

lactate, alanine increase- lactate and inflammatory cytokines impair autoregulation of brain circulation

–› increased filtration of fluid into brain tissue- a fatal complication is herniation of the brainstem - the cause of death of about a

third of patients with acute liver failure

Portal hypertension syndrome I.

- increased vascular resistance in liver microcirculation- venostasis in the portal bloodstream - development of portosystemic collaterals and hyperkinetic circulation in the

splanchnic and systemic bloodstream- increased activity of sympathetic and renin-angiotensin-aldosterone system- alteration of renal perfusion and renal function- ascites formation, pulmonary circulation disorders and heart function disorder- development of hepatic encephalopathy

Portal hypertension syndrome II.

- resistance in the portal bloodstream (gradient between portal vein and hepatic vein increases (clinically significant increase above 12 and more torr - increased risk of serious complications, esophageal variceal bleeding)

- venostasis develops in splanchnic organs, development of splenomegaly, digestive disorders

- increased production of local vasoactive substances with vasodilatory effect- increasing blood flow in portosystemic collaterals with remodeling and increasing

blood flow capacity –› development of portosystemic collaterals- hyperkinetic circulation in the splanchnic region (decrease in resistance

in splanchnic arterioles –› more blood flows in portosystemic collaterals)- hyperkinetic circulation in the systemic bed (low resistance in the splanchnic bloodstream

leads to a decrease in total peripheral resistance)

Water management disorder

- activation of the renin-angiotensin-aldosterone system and ADH- expansion of extracellular fluid, and later decrease in its osmolarity- decrease of kidney perfusion and alteration of their function –›

development of hepatorenal syndrome(functional kidney impairment with a decrease in glomerular filtration and accentation of tubular resorption –› renal failure with oliguria, low natriuresis and urinary hyperosmolarity)

- ascites - accumulation of plasma ultrafiltrate fluid in the peritoneal cavity (increased filtration in liver and reduced resorption)

- discomfort and ventilation disorder in tense ascites- fluidotorax due to pathological communication throught diaphragma septum

and normal pressure gradient between peritoneal and pleural cavity (transudate transfer) –› restrinctive ventilation disorder –› pulmonary complications

- edema - consequence of retention and expansion of extracellular fluid in portal hypertension, hypalbuminaemia, (ev. also cytokines)

- Acute liver failure – develops in acute massive lesion of liver parenchyma –›possible complication – brain edema

- Terminal liver failure – is based on chronic liver disease – mainly leads to multiorgan failure due to circulatory and metabolism disorders

Acute liver failure: p a t h o p h y s i o l o g y- acute damage or destruction of a large mass of liver cells- releasing large amounts of inflammatory cytokines- immune response with massive secondary liver parenchyma damage

- presence of a coagulation disorder (INR greater than 1,5 with any degreeof encephalopathy)

- in patients without cirrhosis (viral hepatitis A, B , C , D and E, herpes simplex), autoimmune hepatitis, hypoxic hepatitis, acute Budd-Chiari syndrome, acute Wilson’s disease, acute pregnancy steatosis

- typically in the field of healthy liver tissue based on exposure to a hepatotoxic agent or triggering a pathological mechanism

- in some cases - also by acute insult in the field of chronic liver disease(Wilson’s disease, chronic autoimmune hepatitis, delta agent superinfectionin chronic hepatitis B)

O´Grady classification of liver failure:

Hyperacute liver failure: interval icterus - encephalopathy: 1 week (35 % survival)

Acute liver failure: interval icterus – encephalopathy: 2-4 weeks (10 % survival)

Subacute liver failure: interval icterus – encephalopathy: 2-12 weeks (15 % survival)

Clinical forms of acute liver failure according to the rapidity of development:

Hyperacute

Acute

Subacute

.............................................................................................................................

or

Fulminant

Subfulminant

- (some importance for prognosis)

Clinical signs of acute liver failure

- are related to the rapidity of development of the condition

- nonspecific initial symptoms

- icterus and encephalopathy

- insufficient liver detoxification function

- insufficient hepatic proteosynthetic function

- disturbance of humoral regulation

- disturbance of immune functions

- brain edema

- sepsis

- circulatory dysfunction and impaired regulation of intravascular circulation

- disturbance of the internal milieu

Chronic liver failure: p a t h o p h y s i o l o g y

- it develops on the basis of chronic liver disease with gradual loss of liver tissue function

- typical example: cirrhosis - functional tissue is replaced by connective tissue due to inflammatory process - may reach a status of critical liver function insufficiency

- more frequent intercurrent complications exceed current liver function reserve –›development of liver failure (e.g. surgery, acute GIT bleeding, sepsis)

- gradual development of liver insufficiency

- development of hepatic encephalopathy

- brain edema is not present

- metabolic and hormonal disorders –› decreased trophics of skin, subcutaneous tissue and muscles, gynecomastia, impotence, infertility, amenorrhea

- complications of portal hypertension (bleeding from esophageal, gastric or ectopic varices, or gastropathy, ascites, spontaneous bacterial peritonitis, hyponatraemia, hepatorenal syndrome, portopulmonary hypertension, cirrhotic cardiomyopathy)

- septic complications

Acute failure in the field of chronic liver disease: p a t h o p h y s i o l o g y

- acute severe liver disorder caused by various insults in chronic patients with liver disease or cirrhosis

- it is acute liver failure due to chronic liver disease (ACLF)

- serious acute worsening of chronic liver disease based on acute complications of the disease (e.g., sepsis, acute alcoholic hepatitis, etc.) which endanger the patient and there is the possibility of multiorgan failure and death within about 4 days

- in almost half of the cases the inducing factor is not recognized

- there is always a systemic inflammatory response that has a negative impact on already impaired function of vital organs and systems – (mainly kidneys, haemocoagulation, brain, circulation and lungs,) –› mortality – up to 50% within 4 weeks and about 65% within 3 months

- thus, it differs from the simple decompensation of liver cirrhosis by a high short term mortality

- imitates acute liver failure

A c u t e l i v e r f a i l u r e I.

- a severe condition characterized by the unexpected development of signs of liver failure in patients with no previous history of liver disease (i.e. in a healthy liver to date)

- is accompanied by a disorder of consciousness and coagulopathy

- It is not an acute liver failure due to unexpected worsening of chronic liver disease (acute-on-chronic liver failure - ACLF ) – which also has high mortality

- distinguishing acute liver failure from ACLF is sometimes difficult (e.g. alcoholic hepatitis)

- there is a significant impairment of liver function (mainly synthetic) in relative a short period with rapid onset of encephalopathy

- impaired function is due to the death of hepatocytes for various reason

- short course – if the patient survives, there is no chronic liver damage

- prevalence fluctuates – 15-20 /100 000 inhabitants

- in the United States the incidence is 2300-2800 cases per year

A c u t e l i v e r f a i l u r e II.

- characteristic:

- coagulation disorder (INR mostly over 1.5 with any degree of encephalopathy in patients without cirrhosis),

- or the development of encephalopathy within eight days of the onset of icterus (but sometimes the icterus may not necessarily be present)

- very rapid onset of disease – if etiological factors can be influenced – (if adequately treated) – has a better prognosis – does not occur significantly morphological damage of hepatocytes – liver function can be repaired ad integrum

- in acute liver failure due to hepatitits A, ev. paracetamol intoxication – there is more than 50% chance of spontaneous survival

- if Wilson’s disease is the cause – the possibility of spontaneous survival is zero

- overall : conservative treatment – less than 20% survival,

- in transplantation – increase of survival to about 65%

A c u t e l i v e r f a i l u r e III.

- Examination:

- history

- determination of the cause (dif.dg: Wilson’s disease, intoxication, viral infection, etc.)

- prothrombin time, coagulation factors, glycaemia, electrolytes, urea, creatinine, bilirubin, aminotransferases, obstructive enzymes, supplementary liver diagnostic tests, blood gases, blood count, diuresis, ECG

- sputum, tampons, urine for cultivation, hamoculture, virological examination

- examination of antigens, antibodies

- intracranial pressure

- chest X-ray

- CT, MR if necessary

A c u t e l i v e r f a i l u r e IV.

- Clinical symptoms:

- icterus, weakness, nausea, abdominal pain

- consciousness disorder – qualitative later also quantitative

- abnormal neuromuscular activity - often

- failure of many organs after reduction of functional liver volume (sepsis, toxic poisoning effects, etc. )

- renal failure and severe respiratory and cardiovascular involvement with subsequent lack of oxygen in the tissues is often present

- the clinical picture remind septic shock, acute respiratory distress syndrome (ARDS) or pulmonary edema

- liver failure leads by a number of mechanisms to coagulopathy, metabolic complications (hypoglycaemia, acid-base balance disorders), sometimes to portal hypertension

Classification of hepatic encephalopathy

- Stage I: euphoria, or opposite - depression, mild confusion,

bradypsychism, sleep disorders, asterixis

- Stage II: escalation of previous difficulties, somnolence, incontinence

- Stage III. sopor, does not cooperate upon awakening, or is restless,

desorientation, confused

- Stage IV. coma

A c u t e l i v e r f a i l u r e – p r o c e d u r e s a)

- Cerebral complications:

- encephalopathy – basic symptom of acute hepatic failure, prognostic indicator, indicator for liver transplantation

- increase of intracranial pressure – basic pathophysiological mechanism of damage CNS in acute liver failure

- efforts to prevent intracranial hypertension –› try to resolve situations that lead to it (fever, hypertension, restlesness)

- monitor clinical signs of increased intracranial pressure – abnormalities of the pupils

- intracranial pressure monitoring

- manitol 0,5-1g/kg weight –› repeatedly and simultaneously osmolarity monitoring

- in encephalopathy III-IV. stage - patients are on controlled ventilation

A c u t e l i v e r f a i l u r e – p r o c e d u r e s b)

- Cardiovascular disorders

- attempt to keep hemodynamic stability by monitoring and conditioning of central venous pressure and mean arterial pressure

- hypotension is a serious finding

- correction of hypovolaemia is necessary –› colloidal solutions and crystalloids

- in the persistence of hypotension –› vasopressors - adrenaline, noardrenaline

- on failure eventually add terlipressin

- cardiac arrhythmias are possible (unless electrolyte and acid-base balance is corrected)

A c u t e l i v e r f a i l u r e – p r o c e d u r e s c)

- Renal disorders

- impaired renal function is frequent (40-85% of cases)

- avoid nephrotoxic drugs (e.g. aminoglycosides)

- it is important preservation of renal perfusion in hypotension

- small doses of dopamine (2-4 ug/kg/min.) may be beneficial

- haemodialysis is often necessary but leads to an increase in intracerebral pressure

- more preferred is continuous a-venous perfusion and haemofiltration

- Sepsis

- in acute hepatic failure 70% is caused by a gram-positive bacteria (35% staphylococcus aureus ) –›

- 3rd generation cephalosporins with vancomycin

- in protracted course –› often occur fungal infections

A c u t e l i v e r f a i l u r e – p r o c e d u r e s d)

- Coagulopathy

- coagulation disorders are common – prothrombin time is an important prognostic indicator

- to prevent gastrointestinal bleeding –› by proton pump inhibitors

- vitamine K

- Hypoglycaemia

- regular finding –› requires monitoring

- correction by continuous glucose infusions

- Disorders of water and electrolyte balance

- regular monitoring is necessary

- both sodium and water clearance are decreased

- initially mostly hypokalaemia –› need for substitution, later possible hyperkalaemia

- more suitable haemodiafiltration than haemodialysis to correct hypervolaemia

- enteral or parenteral nutrition – in patients with III. and IV. stage of encephalopathy

A c u t e l i v e r f a i l u r e – p r o c e d u r e s e)

- I. Non-specific treatment of complications in specialized centers

- II. Extracorporeal support

- III. Liver transplant

- Treatment by cause:

- Acute liver failure due to v i r a l i n f e c t i o n s

- Acute liver failure due to t o x i c r e a s o n s

- Acute liver failure due to v e s s e l r e a s o n s

- Acute liver failure due to m e t a b o l i c d i s e a s e s and a c u t e p o r p h y r i a

A c u t e l i v e r f a i l u r e – p r o c e d u r e s f)

EXTRACORPORAL SUPPORT

- previous procedures for removal of exo – and endotoxins (haemodialysis, haemoperfusion, plasma exchange ) – nonspecific, relatively unsuccessful

- MARS, Prometheus, Teraklin AG, Fresenius – combination of albumin and conventional dialysis (extracorporal system of so-called albumin dialysis ) – uses human serum albumin as selective adsorbent for removal and transport of toxins – use of specific membrane for selective removal of free and albumin-bound toxins (the patient blood is passed through an albumin-impermeable hollow fibres dialyser), -

- the dialysate contains human albumin which binds membrane-diffusing molecules, - the albumin-bound molecules in the dialysate are removed when passing through an activated carbon column and an anion exchange column, -

- which also results in conventional dialysis, which removes the low molecular weight dialysable ions

- bio-artificial liver BAL, extracorporeal liver assist device (ELAD), extracorporeal liver support system (ELSS ) - perspective

- combination of techniques – in one device: high volume haemofiltration, continuous plasma-adsorption (coupled plasma filtration adsorption - CPFA ) and continuous sepsis attenuating therapy (CAST)

A c u t e l i v e r f a i l u r e – p r o c e d u r e s g)

- A c u t e l i v e r f a i l u r e c a u s e d b y v i r a l i n f e c t i o n s

Fulminant hepatitis caused by enteroviruses – hepatitis A and E viruses

- viral hepatitis A – formerly considered a disease with benign course

- a sporadic, more serious course in adults is present in this time

- accounts for about 20% of all fulminant hepatitis in Europe

- the risk of acute liver failure increases with age

- there is an increase in prolonged or relapsing forms with extrahepatic symptoms (arthritis, vasculitis)

- the patients have high IgM antibodies titer (only about 5 % - the first days -serologicaly negative – the investigation is necessary repead)

- viral hepatitis E - in case last trimester gravidity –› high mortality (up to 20 %)

- investigation of IgG a IgM antibodies and HEV RNA by PCR method

A c u t e l i v e r f a i l u r e – p r o c e d u r e s h)

- A c u t e l i v e r f a i l u r e c a u s e d by v i r a l i n f e c t i o n s

Fulminant hepatitis caused by hepatitis B, C and D viruses

- hepatitis B takes part in fulminantly occuring forms of the disease worldwide

- the risk of serious form increases with co-infection with hepatitis D or C

- higher incidence of fulminant course - in patients after cytotoxic or immunosuppressive therapy

- higher incidence of fulminant course – even in patients with chronic hepatitis B concomitantly treated with immunosupressants –› (the need for concomitant administration of nucleoside analogues – prevention flare of disease)

- necessary examination anti HBcIgM, HBsAg, anti HBs, HBV DNA by PCR method

- co-infection or superinfection with hepatitis D virus – associated with increased risk of fulminant course - but lower mortality

- determination of delta antibodies – necessary in unclear cases

- in developed countries - isolated hepatittis C infection – is rarely the cause of fulminant liver failure

- in developing countries - hepatic failure – more often in immunodeficient patients

A c u t e l i v e r f a i l u r e – p r o c e d u r e s i)

- A c u t e l i v e r f a i l u r e c a u s e d b y v i r a l i n f e c t i o n s

Fulminant hepatitis caused by systemic viral infections

- fulminant failure – herpes viruses in developed countries (herpes simplex, varicella zoster) - possibility of treatment by acyclovir

- yellow fever and other arbovirus infections in tropical areas

- cytomegalovirus and Epstein-Barr virus – a problematic role in fulminant failures

- basis of diagnosis: establishing extrahepatic disease signals in patients with negative

serological findings for conventional viral hepatitis

A c u t e l i v e r f a i l u r e – p r o c e d u r e s j)

- A c u t e l i v e r f a i l u r e c a u s e d b y t o x i c r e a s o n s

- the liver has important role in the biotransformation of xenobiotics

- it is exposed to a number of potentially toxic substances and metabolites (natural alkaloids and alcohols, mycotoxins, industrial chemicals, drugs etc.)

- possible liver involvement – from asymptomatic abnormalities to fatal liver necrosis

by mechanism of action hepatotoxic substances:

- primary hepatotoxins

- idiosyncratic (secondary) hepatotoxins

- Primary hepatotoxins - mainly cause zonal necrosis in a short time (several days) -dose-dependent effect (paracetamol, ammanita phalloides toxins, some industrial solvents etc.)

- Idiosyncratic hepatotoxins–they cause liver damage through their metabolites in susceptible individuals – in connection with variability of biotransformation pathways, hypersensitivity or a combination of both – the disability is manifested after a relatively long time and is not dose-dependent

A c u t e l i v e r f a i l u r e – p r o c e d u r e s k) - A c u t e f a i l u r e c a u s e d b y t o x i c r e a s o n s

Paracetamol poisoning 1)

- paracetamol – a synthetic derivative of p-aminophenols – component of numerous analgetics and antipyretics

- biological half-life is 12 h, in 98% it is metabolized in the liver

- one of its toxic intermediate metabolites is reduced by the sulfhydryl group of glutathione to a non-toxic form

- high dosing –› relative glutathione deficiency –› cell protein binding –› centriolobular necrosis

- minimal toxic dose in adults: 5-15 g, acute lethal dose 13-25 g

- Clinical course of paracetamol poisoning – several phases:

- Initial phase: 0-24 h after ingestion – minimal symptoms, possible nausea and vomiting

- Intermediate phase: 24-48 h after ingestion – elevation of aminotransferases, often metabolic acidosis

- Phase of manifestation of liver damage: 3-4 days after ingestion: symptoms of acute liver failure – icterus, bleeding, encephalopathy, possible acute pancreatitis, arrhythmias, ECG abnormalities

- Recovery phase: if survives – normalization of laboratory findings within 5 days, histology within 3 months

A c u t e l i v e r f a i l u r e – p r o c e d u r e s l)

- A c u t e f a i l u r e c a u s e d b y t o x i c r e a s o n s

Paracetamol poisoning 2)

- complementary examinations: medical history and quantitative analysis of paracetamol levels (therapeutic levels – 5-20 mg/l, damage at levels over 200 mg/l )

- high levels of aminotransferases, low level of bilirubin, low level of arterial pH –›considering of sending to the transplant center

- therapy: toxin elimination and antidote administration

- toxin elimination: gastric lavage, activated charcoal 10-20 g every 4 hours

- antidote –N-acetylcysteine – a precursor of glutathione –› will increase its synthesis and possibility of detoxification of toxic metabolites

A c u t e l i v e r f a i l u r e – p r o c e d u r e s m)


Ammanita phalloides poisoning 1)

- Amanita phalloides – contains 3 groups of toxins – the most important are amanitins -(especially alpha-amanitine) – are potent inhibitors of protein synthesis in the cell (by inhibition or RNA polymerase II) –› most damaging cells with high replication and the possibility of direct contact with the toxin (liver, kidney, intestinal)

- in intoxication – histologically massive centrilobular necrosis in the liver –› toxins are rapidly absorbed, enterohepatic cycle and glomerular filtrate resorption increase toxicity

- after binding of the toxin to the cell polymerase –› cell damage can no longer be prevented

- Ammanita contains 2-3 mg amanitin/g dry weight – lethal dose may be 50 g of mushroom (1-3 fruiting bodies)

A c u t e l i v e r f a i l u r e – p r o c e d u r e s n)



- Clinical course: poisoning – in several periods:

- Asymptomatic state: the first symptoms appear only 6-24 hours after ingestion (usually 10-12 hours) - the time necessary for binding to RNA polymerase II.

most non-lethal fungal poisoning mainly causes gastroenteritis - has a faster onset -better prognosis. Late onset is always alarming.

- Gastrointestinal phase: watery diarrhea often with blood, nausea, vomiting, severe abdominal pain - intestinal cell damage, high fever, dehydration, tachycardia (usually lasts 24 hours)

- Latent phase: alpha-amanitin accumulates in hepatocytes –› elevation of aminotransferases, remission of gastrointestinal complaints (lasts 12-24 hours )

- Hepatorenal phase: - occurs 3-4 days after ingestion of fungi - signs of liver failure, mainly icterus and stage 3 to 4 encephalopathy, mostly also kidney failure. Mortality 10-40 % (according to ingested dose, patient condition and individual susceptibility)

A c u t e l i v e r f a i l u r e – p r o c e d u r e s o)



- Complementary examinations: to be monitored:

- aminotransferases – significant elevation (mainly AST), glycaemia (hypoglycaemia),

- ammonia - increase

- serum amylase (cca in 50 %) increase

- bilirubin, creatinine, urea, minerals, prothrombin time, blood count

- mycological examinations: fungi residues

- Therapy: condition stabilization and decontamination

- substitution of liquids and ions

- glucose solutions

- elimination of noxis from gastrointestinal tract (gastric lavage) activated charcoal –large doses over 48 hours (20-40 g), lactulose

- elimination methods: stimulative diuresis, haemoperfusion, albumin dialysis within 24-30 hours

- haemodialysis in renal failure

A c u t e l i v e r f a i l u r e – p r o c e d u r e s p)



- Liver cell protection

- Penicillin G – benzylpenicillin at high doses (1 million units/kg/day i.v.) for several days until the aminotransferases decrease

- silibinin (the most active component of silymarin) has a protective effect on the cell membrane of 20-50 mg/kg/day in 4 daily doses

- other options: thioctic acid (is a coenzyme of Krebs cycle) 50-150 mg every 6 hours,

N-acetylcysteine – currently – also to be considered

- liver transplantation – in case of development of fulminant failure – consideration by assessment of severity according to King’s College criteria

- liver failure treatment

Hepatic impairment by idiosyncratic hepatotoxins a)

- pharmacological damage – often clinically serious, sometimes difficult to prove

- they usually do not cause acute liver failure

- morphologically – in this type of drug-related damage – a number of disorders:

- non-specific focal hepatitis with limited cell necrosis (acetylsalicylic acid, oxacillin )

- hepatitis-like reaction, diffuse hepatocellular degeneration and necrosis with variable inflammatory changes (halothane, isoniazid, methyldopa)

- cholestasis (estrogens, androgens, anabolic steroids, phenothiazine, augmentin, oral antidiabetics, macrolide antibiotics)

- steatosis – increases deposition of triglycerides in the liver cell (alcohol)

- granulomatous changes – often accompanied by extracellular granulomas (phenylbutazone, quinidine, allopurine)

- fibrosis (methotrexate, hypervitaminosis A)

- benign tumorous changes, most commonly adenoma (some contraceptives)

- vascular changes – hepatic vein thrombosis (contraceptives, azathioprine)

- chronic hepatitis with a histological finding similar to viral hepatitis /prolonged use of certain drugs/ (amiodarone, isoniazid, methyldopa, diclofenac, phenytoin,nitrofurantoin)

Hepatic impairment by idiosyncratic hepatotoxins b)

- Diagnostics and therapy:

- diagnosis is often difficult – liver damage by drugs – often similar to liver diseases of other etiology (viral hepatitits, biliary tract diseases)

- many drugs can also cause more than one morphological damage

- the most important is the medical history (including the search for industrial toxins) and the recovery after discontinuation of drugs

- complementary investigations tend to be non-specific

- liver biopsy may be beneficial

- the most important is discontinuation of the drug

- discontinue any medication that is not unavoidable

- corticosteroids can have an effect

- considering also N-acetylcysteine

The most common drugs causing long-term liver damage 1.

Amiodarone

- it can cause a slight increase in aminotransferases – they usually normalize over time

- 1-3% of patients – possible development of severe hepatic impairment (histologically similar to acute alcohol hepatitits)

- the benefit of liver biopsy

- possible persistence of damage – even several months after treatment is discontinued

- possible progression to micronodular liver cirrhosis

Augmentine

- combination of amoxicillin and clavulanic acid – possible cholestatic liver damage

- clinical manifestations often occur several weeks after discontinuation of treatment –resolves within 4-6 months after discontinuation

- it more often affects older men


Erythromycin

- it can cause acute inflammatory cell changes, often necrotic

- clinically, it can imitate acute cholecystitis or cholangitis

- symptoms resolve after discontinuation in a few days

Halothane

- may rarely cause symptoms similar to viral hepatitis (7-10 days after exposure)

- fever, rising icterus, event. coagulation disorder

- possible progression into massive liver necrosis

- women and obese elderly patients are more vulnerable

- Isoniazid

- it can cause subclinical liver damage in 10-20% of patients

- slight increase in aminotransferases – first weeks of treatment

- rarely, severe liver damage is possible in 1-2 months in 1% of patients

- clinical and histological similarity to viral hepatitis


Methyldopa

- it may cause similar symptoms to isoniazide at the start of treatment in 6% of patients

- rarely, severe liver damage is possible

Peroral contraceptives

- they may in a small percentage of cases, cause a series of liver damage:

- hepatocellular cholestasis

- increased predisposition to hepatic vein thrombosis

- increased predisposition to gallstone formation

- possible formation of adenoma

- probably – genetic predisposition (more common in some populations)

- Fenytoine

- may be rare - (6 weeks after starting treatment) - symptoms similar to viral hepatitis

A c u t e l i v e r f a i l u r e d u e t o v a s c u l a r c a u s e s

If acute liver failure shows signs of ischemic liver parenchyma it is necessary:

To optimize liver perfusion:

substitution of intravasal volume

obtaining sufficient mean arterial pressure

- Budd-Chiari syndrome – an example of acute liver failure

- complex disease caused by thrombotic occlusion of large central liver veins

- possible causes: clotting disorders leading to the induction of a thrombophilic state(antithrombin III deficiency, activated protein C resistance, thrombocytosis, polycythaemia vera, paroxysmal nocturnal haemoglobinuria, myeloproliferative diseases, etc. )

- congestion and necrosis in the liver parenchyma and congestion throughout the splanchnic bloodstream

- depending on the clinical extent – acute, subacute, or chronic disease

- the acute manifestation resembles a fulminant failure

- chronic forms resemble liver cirrhosis of unclear cause

A c u t e l i v e r f a i l u r e c a u s e d b y m e t a b o l i c l i v e r d i s e a s e s 1.

- Metabolic diseases are rarely the cause of acute liver failure (0,2-0,65 %).

They rather affect children and younger people (fulminant manifestation of Wilson’s disease, acute cholestasis in pregnancy, Rey’s syndrome).

Fulminant manifestation of Wilson’s disease:

- it is an autosomal recessive hereditary disease

- copper cumulation in organs (especially liver, brain)

- variety of clinical findings – the most serious is the fulminant form (8% of all causes) –mostly women

- diagnostics: other causes of fulminant failure should be differentiate

- extreme hyperbilirubinaemia is typical (400-700 umol/l and low alkaline phosphatase(the ratio of ALP to bilirubin is less than 2)

- regularly – hemolytic anemia (releasing quantum of Cu from the necrotizing liver –› blocks enzymes and lowers the level of reduced glutathione),

- aminotransferases – only slightly increased, AST/ALT ratio higher than 4


Fulminant manifestation of Wilson’s disease:

- rapid progressive coagulopathy (INR above 2,5)

- frequent renal failure,

- high Cu excretion in urine

- Cu in serum – elevated (in other forms of Wilson’s disease is reduced) -

because high fraction of free Cu in serum - released from destructed hepatocytes

- ceruloplasmin is not reduced – (is surprisingly within the normal range)

- Kayser-Fleischer ring - present in a minority of patients

- high Cu in the liver - examination of Cu levels in the liver parenchyma - only transjugular biopsy possible

- in majority of patients– cirrhosis is already present

- urgent liver transplantation - necessary


Rey’s syndrome:

- acute disease characterized by encephalopathy and fatty liver infiltration

- most often in children under 10 years, 20% in children over 15 years, sometimes adults

- related to the administration of acetylsalicylic acid in virosis and varicella

- (salicylates are capable of inhibiting the oxidation of long chain fatty acids)

- elimination of acetylsalicylic acid in children - decrease in disease incidence

- symptoms of virosis, later vomiting, psychological changes - possible progression to coma

- unclear cause of liver and brain damage

- acute encephalopathy, increase in ammonia, great increase in aminotransferases (3-50 times)

- massive microvesicular-type fat infiltration and glycogen decline with minimal hepatocellular necrosis

- bilirubin normal, or slightly increased, prothrombin time prolonged

- possible neurological consequences (in 30 %), mortality from 2 to 80 %

- necessary treatment of hypoglycaemia, correction of electrolyte disorders, treatment of intracranial hypertension


Acute porphyria:

- Porphyria – excessive formation and secretions of porphyrins and their precursors due to enzymatic blockade

- liver – the main site of haem biosynthesis, as well as the site of excretion of porphyrins

- Classification of porphyria:

- by site of accumulation: erythropoietic and hepatic

- by the clinical course: acute and chronic

- acute porphyria is less common than chronic

- intermittent course and increase of ALA synthase activity

- acute attacks induced after a symptom-free period (various stimuli: alcohol, starvation, carbohydrate deficit, hormones, stress, drug intoxication, etc.)

- in acute porphyria– gastrointestinal and neurological-psychiatric complications

- basis of diagnosis: clinical symptomatology, excretion of porphyrins and their precursors in urine and faeces, determination of their plasma concentration


- Acute porphyria:

Acute porphyria in the delta-amino-levulinic acid dehydratase deficiency (ALA)

Acute intermittent porphyria

Hereditary coproporphyria

Porphyria variegata

Acute intermittent porphyria(AIP):

- the second most common porphyria– 3-4 x times more common in women

- the most common manifestation between the 20-40th year of life

- autosomal recessive hereditary disease (porfobilinogen deaminase deficiency)

- genetic defect - on the chromosome 11q23

- gene frequency - geographically highest occurrence in the Nordic countries (Denmark, Finland, Sweden, United Kingdom)

- first manifestation – related to the pre-menstrual phase after a number of different stimuli


Acute intermittent porphyria (AIP) a):

- clinically 5 basic symptoms:

- cardiovascular: tachycardia, hypertension, ECG changes, cardiac complaints resemble a thyreotoxic crisis (20% of patients also have FT3 and FT4 elevation)

- abdominal pain of colic type - more often in the lower abdomen, vomiting, subileus similarity picture

- significant constipation not responding to medication

- peripheral neuropathy – muscle paralysis and paresis

- neuropsychotic difficulties– depression, anxiety, hallucination, delirium or coma

- findings: often hyponatraemia with the development of encephalopathy, hypochloraemia, sometimes hypokalaemia and hypomagnesaemia, frequent oliguria

- often elevations of aminotransferases and bilirubin (intermediate values)

- red urine (the color of burgundy wine) – darkens on standing

- urinary multiple excretion of porphobilinogen and delta-aminolevulinic acid in urine


Acute intermittent porphyria (AIP) b):

- decreased erythrocyte porphobilinogen deaminase activity (but even normal activity does not rule out disease – can only be reduced in the liver)

- presence of ultrastructural changes of hepatocytes – liver steatosis and siderosis

- differential diagnosis: acute abdomen, ileus, pancreatitis, peritonitis, polymyelitis, hysteria, psychosis, myocardial infarction

- the prognosis variable – but severe – acute attack may result in fatal outcome

- peripheral paresis on hands and feed after an active attack

- in the therapy eliminate all drugs, regulation of water and electrolyte balance, high doses of chloropromazine, suitable beta-blockers

- hemarginate infusions (Normosang) 3 mg/kg/day over 4 days

- glucose infusion 4x500 ml 20 % glucose daily

- for peripheral paresis – consider prednisone 100 mg/day, plus omeprazole

- between seizures eliminate suspicious medications


Porphyria variegata:

- defect of protoporphyrinogen oxidase

- autosomal dominant transmission, defect located on the 14th chromosome

- combination of skin changes with symptoms of acute intermittent porphyria

- high levels of total porphyrins, including porphobilinogen and ALA mainly in acute attack

- increased amount of excreted coproporphyrin in faeces and urine also in the preclinical phase

- inducing factors like acute intermittent porphyria

Hereditary coproporphyria:

- defect of coproporphyrinogen oxidase

- autosomal dominant transmission, defect located on the 9th chromosome

- very rare disease, form with acute attacks – very rare

- increased urinary excretion of porphyrins, especially coproporphyrin and protoporphyrin

- skin symptoms with photosensitivity, hypertrichosis and pigmentation – in 30% of patients

- in an acute attack, an image similar to an acute intermittent porphyria

- liver biopsy fluoresces red (high cumulation of porphyrins in the liver)

T h a n k y o u

f o r

y o u r a t t e n t i o n

Prof. MUDr. Viera Kupčová, CSc.

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Transcript of Prof. MUDr. Viera Kupčová, CSc.