15 - Clinical Aspects of Energy and Metabolism 1

What are the two main amino acids responsible for carrying nitrogen back to the liver from peripheral tissues? Explain a bit

1. Alanine: From skeletal muscle, once it gets to liver, reacts with alpha keto glutarate to form pyruvate and glutamate(Undergoes oxidative deamination to give ammonia to urea cycle)

2. Glutamine: From other peripheral tissues, carries 2 nitrogens, both released to give ammonia to urea cycle

Describe the progression of the spectrum of liver disease

1. Acute hepatitis: sudden inflammation

2. Chronic hepatitis: ongoing inflammation lasting over 6 months

3. Cirrhosis: Scarring from fibrosis that causes permanent structural changes, end stage chronic liver disease

4. Hepatocellular Carcinoma(HCC): Liver cancer

What is cirrhosis and how does it impair normal liver function?
Fill in the effects for each category:

• Protein synthesis: ___

• Detoxification: ___

• Immunity: ___

• Bile production: ___

• Nutrient metabolism: ___

• Storage: ___

Cirrhosis is the end-stage of chronic liver disease, marked by fibrosis and regenerative nodules. It impairs liver function across multiple systems:

• Protein synthesis: ↓ Albumin → fluid leaks due to less osmotic pressure → edema, ascites; ↓ clotting factors → bleeding risk

• Detoxification: ↑ Ammonia → hepatic encephalopathy; ↑ Estrogen → gynecomastia, spider nevi

• Immunity: Dysfunctional Kupffer cells → bacterial translocation, ↑ risk of infections (e.g. SBP)

• Bile production: ↓ Bilirubin clearance → jaundice, pruritus

• Nutrient metabolism: Impaired handling of carbs, fats, proteins → fatigue, hypoglycemia

• Storage: ↓ Glycogen, vitamins (esp. A), and minerals → malnutrition, low energy

What is ascites, and what causes it in cirrhosis?

Buildup of fluid in abdominal cavity, due to lower albumin and portal hypertension

What is coagulopathy and why does it occur in cirrhosis?

Impaired blood clotting due to decreased production of clotting factors by liver

What is hepatic encephalopathy, and what causes it?

Brain dysfunction caused by impaired detoxification which leads to ammonia buildup in brain

What is gynecomastia, and why does it happen in cirrhosis?

Development of male breast tissue due to increased estrogen thanks to liver dysfunction

What is jaundice, and what causes it in cirrhosis?

Yellowing of skin and eyes due to increased bilirubin buildup due to less bile excretion

What is pruritus, and why does it occur in liver disease?

Itching caused by bile salt accumulation

What is palmar erythema, and what causes it in cirrhosis?

Reddening palms caused by increased estrogen levels

What is clubbing, and how is it related to liver disease?

Bulbous enlargement of fingertips, exact cause in cirrhosis unsure

What is Dupuytren’s Contracture, and how does it present in liver disease?

A contracting of the ring finger due to fibrosis of palmar fascia

What are spider nevi, and what causes them in cirrhosis?

Small, red, spider-like lesions on skin caused by estrogen-induced vasodilation

What is asterixis, and what causes it in cirrhosis?

Also called flapping tremor, when the wrist flaps down when we try to hold it up, often a result of ammonia induced brain dysfunction

What is portal hypertension, and how is it caused by cirrhosis?

In cirrhosis, the fibrotic scar tissue blocks blood flow, causing increased pressure in portal vein

What is hepatitis B, and how does it differ from hepatitis C? Why is hepatitis B the most common cause of cirrhosis in Thailand?

Hepatitis B is a bloodborne virus that can cause chronic liver inflammation, especially when transmitted at birth.
Hepatitis C also causes chronic liver disease, but it spreads mainly through blood and has no vaccine, though it can be cured with antivirals.
Hepatitis B is the most common cause of cirrhosis in Thailand because many people were infected early in life, before vaccination became routine.

What is hepatic encephalopathy (HE) in cirrhosis, and what is the pathogenesis?

When ammonia buildup causes brain dysfunction due to the liver not being able to detoxify ammonia, allowing it to stay in blood, or the blood bypassing the liver through shunts until it reaches the brain

How does ammonia, glutamine, aromatic amino acids and branched chain amino acids contribute to HE pathogenesis in cirrhosis?

Ammonia: Crosses blood brain barrier, astrocytes trap them and form glutamine via glutamate + NH3 which increases cerebral edema and cell swelling

Aromatic Amino Acids: Cirrhosis leads to AAAs being unable to be metabolized, allowing them to accumulate and form false neurotransmitters which disrupts brain signalling

Branched Chain Amino Acids: Depleted in cirrhosis as they are used for energy, but typically would help restore BCAA/AAA ratio and activate mTOR to promote anabolism and protein synthesis

What are the gut-targeting treatments for hepatic encephalopathy, and how do they work?

1. Lactulose: A synthetic sugar with no digestive enzymes for it, so it becomes lactic acid in the colon, reacting with the ammonia in there to become ammonium, which isn’t absorbed and is excreted(Laxative effect to help clear out ammonia too)

2. Non-absorbable antibiotics(like rifaximin): Antibiotics that don’t get absorbed into the body, stay to kill the ammonia producing bacteria

Why is there even ammonia in the gut?

It is produced by bacteria that breakdown proteins and nitrogenous compounds in the colon

What is LOLA, and how can it treat hepatic encephalopathy?

L-ornithine L-aspartate, used to speed up urea cycle via providing substrates

Why are BCAA supplements used in cirrhosis?

Cirrhosis patients often are malnourished due to bloating forcing them to eat less, and because of that BCAAs are used by skeletal muscle to provide energy(and detoxify ammonia) which causes muscle breakdown, so we need to supply them with BCAA

Name 2 BCAA supplements and contrast them

Aminoleban and Livact, both increase BCAAs, but Livact tastes better however it has no calories, so patients taking Livact must intake calories elsewhere to prevent the BCAAs from just being metabolized into energy

Why are late-night snacks important for cirrhosis patients?

Their impaired livers prevent blood sugar maintenance(worse glycogenolysis, gluconeogenesis) etc so fasting periods like sleep can cause hypoglycemia or muscle breakdown, so eating something before bed can increase fed period and blood glucose

What is sarcopenia, why is it relevant in cirrhosis?

The loss of skeletal muscle mass/strength due to malnutrition and protein breakdown

What is the first line and add-on treatment for HE grades 1-2?

• Lactulose then rifaximin

What should be done for patients with HE grades 3-4?

These patients could have severe confusion or coma, so ICU admission is required for airway protection and close monitoring