Chronic Liver Failure II

Question 1

What situations can hepatic encephalopathy arise fom?

Answer 1

• Acute Liver failure
• Portosystemic shunt without liver failure
• Chronic Liver failure (most common)

–Precipitated (by dehydrting with diuretics e.g.)

–Spontaneous

–Recurrent (with mx hospitalizations)

Question 2

What is hepatic encephalopathy?

Answer 2

Hepatic encephalopathy (HE) is the occurrence of confusion, altered level of consciousness, and comas a result of liver failure. In the advanced stages it is called hepatic coma or coma hepaticum. It may ultimately lead to death.

Question 3

What causes hepatic encephalopathy?

Answer 3

In healthy subjects, nitrogen-containing compounds from the intestine, generated by gut bacteria from food, are transported by the portal vein to the liver, where 80–90% are metabolised through the urea cycle and/or excreted immediately. This process is impaired in all subtypes of hepatic encephalopathy, either because the hepatocytes (liver cells) are incapable of metabolising the waste products or because portal venous blood bypasses the liver through collateral circulation or a medically constructed shunt.

Nitrogenous waste products accumulate in the systemic circulation (hence the older term “portosystemic encephalopathy”). The most important waste product is ammonia(NH3). This small molecule crosses the blood–brain barrier and is absorbed and metabolised by the astrocytes, a population of cells in the brain that constitutes 30% of the cerebral cortex.

Question 4

What happens to the NH3 in astrocytes?

Answer 4

Astrocytes use ammonia when synthesising glutamine from glutamate. The increased levels of glutamine lead to an increase in osmotic pressure in the astrocytes, which become swollen (below). There is increased activity of the inhibitory γ-aminobutyric acid (GABA) system, and the energy supply to other brain cells is decreased.

Question 5

What other things are thought to contribute to the formation of hepatic encephalopathy?

Answer 5

Loss of glutamate transporter gene expression (especially EAAT 2) has been attributed to acute liver failure.

Benzodiazepine-like compounds have been detected at increased levels as well as abnormalities in the GABA neurotransmission system.

• An imbalance between aromatic amino acids (phenylalanine, tryptophan and tyrosine) and branched-chain amino acids (leucine, isoleucine and valine) has been described; this would lead to the generation of false neurotransmitters (such octopamine and 2-hydroxyphenethylamine).
• Manganese – neurotoxin which deposits in the basal ganglia
• Depletion of zinc and accumulation of manganese may play a role.
• Inflammation elsewhere in the body may precipitate encephalopathy through the action of cytokines and bacterial lipopolysaccharide on astrocytes

Question 6

How does Acute Hepatic Encephalopathy (ie. from acute liver injury) present?

Answer 6

W/ Acute liver failure – coagulopathy and altered mental status within two weeks of jaundice

The mildest form of hepatic encephalopathy is difficult to detect clinically, but may be demonstrated on neuropsychological testing. It is experienced as forgetfulness, mild confusion, and irritability. The first stage of hepatic encephalopathy is characterised by an inverted sleep-wake pattern (sleeping by day, being awake at night). The second stage is marked by lethargy and personality changes. The third stage is marked by worsened confusion. The fourth stage is marked by a progression to coma

Question 7

What is a major cause of death with hepatic encephalopathy?

Answer 7

Cerebral edema resulting in cerebral herniation

Question 8

T or F. Hepatic Encephalopathy resulting from crhonic liver injury is more insiduous and slow-forming

Answer 8

T. •Cerebral edema unlikely

Question 9

What are the stages of hepatic encephalopathy based on the West Haven Criteria?

Answer 9

• Grade I –irritability, insomnia, agitation
• Grade II – indifferent, personality change, short term memory impairment, mildly disoriented about time or place
• Grade III – drowsy but arousable, significantly confused and disoriented to time and place
• Grade IV – coma

Question 10

What are some good physical tests that can be used to test for hepatic encephalopathy?

Answer 10

In the intermediate stages, a characteristic jerking movement of the limbs is observed (asterixis, “liver flap” due to its flapping character); this disappears as the somnolence worsens. There is disorientation and amnesia, and uninhibited behaviour may occur. In the third stage, neurological examination may reveal clonus and positive Babinski sign. Coma and seizures represent the most advanced stage; cerebral oedema (swelling of the brain tissue) leads to death.

Encephalopathy often occurs together with other symptoms and signs of liver failure. These may include jaundice, ascites, and peripheral edema. A particular smell (foetor hepaticus) may be detected.

•Myoclonus – with hyperextension of the ankles

Question 11

What is the prognosis of hepatic encephalopathy?

Answer 11

Generally reversible with tx, but permanent brain damage can occur if not tx leading to mild decreases in mentation

• Rarely results in irreversible dementia
• Rarely permanent movement disorders

Question 12

In a small proportion of cases, the encephalopathy is caused directly by liver failure; this is more likely in acute liver failure. More commonly, especially in chronic liver disease, hepatic encephalopathy is caused or aggravated by an additional cause. Name some.

Answer 12

Question 13

Besides addressing underying precipitating factors, how can HE be tx?

Answer 13

• lactulose
• zinc supplementation (a cofactor in NH3 metabolism commonly deficient in liver disease)
• ABX
• address nutrition

Question 14

T or F. The diagnosis of hepatic encephalopathy can only be made in the presence of confirmed liver disease (types A and C) or a portosystemic shunt (type B), as its symptoms are similar to those encountered in other encephalopathies.

Answer 14

T. To make the distinction, abnormal liver function tests and/or ultrasoundsuggesting liver disease are required, and ideally liver biopsy

Question 15

What should be on the DDx for HE?

Answer 15

Seizures

Cerebral hemorrhage

Wilson disease

Meningitis

The diagnosis of hepatic encephalopathy is a clinical one, once other causes for confusion or coma have been excluded; no test fully diagnoses or excludes it

Question 16

What are the subtypes of HE?

Answer 16

Type A (=acute) describes hepatic encephalopathy associated with acute liver failure, typically associated with cerebral oedema

Type B (=bypass) is caused by portal-systemic shunting without associated intrinsic liver disease

Type C (=cirrhosis) occurs in patients with cirrhosis - this type is subdivided in episodic, persistent and minimalencephalopathy

Question 17

How would Types A and B HE be addressed?

Answer 17

If encephalopathy develops in acute liver failure (type A), even in a mild form (grade 1–2), it indicates that a liver transplant may be required, and transfer to a specialist centre is advised.

Hepatic encephalopathy type B may arise in those who have undergone a TIPS procedure; in most cases this resolves spontaneously or with the medical treatments discussed below, but in a small proportion of about 5%, occlusion of the shunt is required to address the symptoms.

Question 18

T or F. Protein intake should be restricted in HE

Answer 18

F. Furthermore, many people with chronic liver disease are malnourished and require adequate protein to maintain a stable body weight. A diet with adequate protein and energy is therefore recommended.

Dietary supplementation with branched-chain amino acids has shown improvement of encephalopathy and other complications of cirrhosis

Question 19

How is lactulose helpful in HE tx?

Answer 19

Lactulose and lactitol are disaccharides that are not absorbed from the digestive tract. They are thought to decrease the generation of ammonia by bacteria, render the ammonia inabsorbable by converting it to ammonium (NH4+) ions, decreased absorption of glutamine, and increase transit of bowel content through the gut.

Doses of 15-30 ml are administered three times a day; the result is aimed to be 3–5 soft stools a day, or (in some settings) a stool pH of <6.0

Question 20

What are some Chronic Neuropsychiatric
complications of cirrhosis?

Answer 20

• Decreased functional capacity despite medical therapy
• Dementia
• Parkinson’s like syndrome
• Cerebral edema rarely

Question 21

How might Hepatic Parkinsonism present?

Answer 21

• Symetrical presentation
• Rigidity
• Often lack a significant tremor

Question 22

T or F. Cerebral edema is more associated with acute liver failure than chronic

Answer 22

T.

Question 23

How does a brain MRI appear in HE?

Answer 23

•Increased intensity in the globus pallidus with T1 weighted MRI

Question 24

What are some common renal diseases assoicated with liver disease?

Answer 24

• Hepatorenal Syndrome
• IgA Nephropathy
• Membranoproliferative glomerulonephritis (hep C)
• Membranous glomerulonephritis (hep C)

Question 25

What is Hepatorenal syndrome (often abbreviated HRS)?

Answer 25

A life-threatening medical condition that consists of rapid deterioration in kidney function in individuals with cirrhosisor fulminant liver failure. HRS is usually fatal unless a liver transplant is performed, although various treatments, such as dialysis, can prevent advancement of the condition

Question 26

What finding highly suggests HRS?

Answer 26

•Lack of return of renal function with intravascular volume repletion suggests

Question 27

There are two types of HRS. Describe Type I

Answer 27

•rapid worsening (creatinine >2.5 mg/dL or decrease in CrCl <20 ml/min within two weeks

Question 28

There are two types of HRS. Describe Type II

Answer 28

•slow progression, often with worsening liver disease

Question 29

• Liver Transplantation
• Hemodialysis until Liver Transplantation

Question 30

What causes IgA Nephropathy?

Answer 30

The disease derives its name from deposits of immunoglobulin A(IgA) in a granular pattern in the mesangium (by immunofluorescence).

There is no clear known explanation for the accumulation of the IgA. Exogenous antigens for IgA have not been identified in the kidney, but it is possible that this antigen has been cleared before the disease manifests itself. It has also been proposed that IgA itself may be the antigen.

•Liver disease is the most common cause of secondary IgA Nephropathy

Question 31

T or F. There is increased deposition of IgA, C3, and other immunoglobulins in 35-90% of cirrhosis patients

Answer 31

T. There is also decreased hepatic clearance of IgA with cirrhosis and portal hypertension (with collateral blood flow around the liver)

Question 32

How does IgA nephropathy present?

Answer 32

The classic presentation (in 40–50% of the cases) is episodic hematuria, which usually starts within a day or two of a non-specific upper respiratory tract infection (hence synpharyngitic), as opposed to post-streptococcal glomerulonephritis, which occurs some time (weeks) after initial infection. Less commonly gastrointestinal or urinary infection can be the inciting agent.

All of these infections have in common the activation of mucosal defenses and hence IgA antibody production. Groin pain can also occur. The gross hematuria resolves after a few days, though microscopic hematuria may persist. These episodes occur on an irregular basis every few months and in most patients eventually subsides, although it can take many years. Renal function usually remains normal, though rarely, acute kidney failure may occur. This presentation is more common in younger adults.

Question 33

Membranoproliferative Glomerulonephritis is commonly seen in what liver diseases?

Answer 33

Chronic Hepatitis C

Question 34

What else is commonly seen with HCV?

Answer 34

•Cryoglobulinemia – abnormal protein in the blood which precipitates with cold temperatures

Question 35